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LEVOFLOXACIN KABI 5 MG/ML SOLUTION FOR INFUSION

Active substance(s): LEVOFLOXACIN HEMIHYDRATE / LEVOFLOXACIN HEMIHYDRATE / LEVOFLOXACIN HEMIHYDRATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Levofloxacin Kabi 5mg/ml solution for infusion.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
50 ml filled in 100 ml bottle/bags:
Each ml of solution for infusion contains 5 mg levofloxacin (as levofloxacin
hemihydrate).
50 ml of solution for infusion contains 250 mg of levofloxacin as active substance.
100 ml filled in 100 ml bottle/bags:
Each ml of solution for infusion contains 5 mg levofloxacin (as levofloxacin
hemihydrate).
100 ml of solution for infusion contains 500 mg of levofloxacin as active substance.
Excipients: The medicinal product contains 3.5 mg of sodium per ml
For the full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM

Solution for infusion.
Yellow to greenish yellow solution

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications
Levofloxacin Kabi solution for infusion is indicated in adults for the treatment of the
following infections (see sections 4.4 and 5.1):



Community-acquired pneumonia.
Complicated skin and soft tissue infections.

For the above-mentioned infections Levofloxacin Kabi should be used only when it is
considered inappropriate to use antibacterial agents that are commonly recommended
for the initial treatment of these infections.



Pyelonephritis and complicated urinary tract infections (see section 4.4)
Chronic bacterial prostatitis



Inhalation Anthrax: postexposure prophylaxis and curative treatment (see section
4.4).

Consideration should be given to official guidance on the appropriate use of
antibacterial agents.

4.2

Posology and method of administration
Levofloxacin solution for infusion is administered by slow intravenous infusion once
or twice daily. The dosage depends on the type and severity of the infection and the
susceptibility of the presumed causative pathogen.
Treatment with Levofloxacin after initial use of the intravenous preparation may be
completed with an appropriate oral presentation as considered appropriate for the
individual patient. Given the bioequivalence of the parenteral and oral forms, the
same dosage can be used.
Posology
The following dose recommendations can be given for Levofloxacin:
Dosage in patients with normal renal function (creatinine clearance > 50 ml/min)
Indication

Daily dose regimen
(according to severity)

Total duration of treatment
(according to severity)
7 - 14 days

1

Community-acquired
500 mg once or twice daily
pneumonia
Pyelonephritis
500 mg once daily
7 - 10 days
Complicated urinary tract
500 mg once daily
7 - 14 days
infections
Chronic bacterial prostatitis 500 mg once daily
28 days
Complicated skin and soft
500 mg once or twice daily
7 - 14 days
tissue infections
Inhalation anthrax
500 mg once daily
8 weeks
1
Treatment duration includes intravenous plus oral treatment. The time to switch
from intravenous to oral treatment depends on the clinical situation but is normally 2
to 4 days.
Special populations
Impaired renal function (creatinine clearance ≤50 ml/min)
Dosage Regimen

250 mg/24h

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 dose is required since levofloxacin is not metabolised to any
relevant extent by the liver and is mainly excreted by the kidneys.
Older People
No adjustment of dose is required in the elderly, other than that imposed by
consideration of renal function (see section 4.4 “Tendinitis and tendon
rupture” and “QT interval prolongation”).
Paediatric population
Levofloxacin is contraindicated in children and growing adolescents (see
section 4.3).
Method of administration
Levofloxacin solution for infusion is only intended for slow intravenous
infusion; it is administered once or twice daily. The infusion time must be at
least 30 minutes for 250 mg or 60 minutes for 500 mg Levofloxacin solution
for infusion (see section 4.4)
For incompatibilities see section 6.2 and compatibility with other infusion
solutions see section 6.6.
4.3.

Contraindications
Levofloxacin Kabi solution for infusion must not be used:







4.4.

in patients hypersensitive to levofloxacin or any other quinolone and any of the
excipients listed in section 6.1,
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.

Special warnings and precautions for use

Methicillin-resistant S. aureus are very likely to possess co-resistance to
fluoroquinolones, including levofloxacin. Therefore levofloxacin is not recommended
for the treatment of known or suspected MRSA infections unless laboratory results
have confirmed susceptibility of the organism to levofloxacin (and commonly
recommended antibacterial agents for the treatment of MRSA-infections are
considered inappropriate).
Resistance to fluoroquinolones of E. coli – the most common pathogen involved in
urinary tract infections – varies across the European Union. Prescribers are advised to
take into account the local prevalence of resistance in E. coli to fluoroquinolones.
Inhalation Anthrax: Use in humans is based on in vitro Bacillus anthracis
susceptibility data and on animal experimental data together with limited human data.
Treating physicians should refer to national and/or international consensus documents
regarding the treatment of anthrax.
Infusion Time
The recommended infusion time of at least 30 minutes for 250 mg or 60 minutes for
500mg Levofloxacin Kabi solution for infusion should be observed. It is known for
ofloxacin, that during infusion tachycardia and a temporary decrease in blood
pressure may develop. In rare cases, as a consequence of a profound drop in blood
pressure, circulatory collapse may occur. Should a conspicuous drop in blood
pressure occur during infusion of levofloxacin, (l-isomer of ofloxacin) the infusion
must be halted immediately.
Sodium content
This medicinal product contains 7.7 mmol (177,1 mg) sodium per 50 ml dose and
15.4 mmol (354,2 mg) per 100 ml dose. To be taken into consideration by patients on
a controlled sodium diet.
Tendinitis and tendon rupture
Tendinitis may rarely occur. It most frequently involves the Achilles tendon and may
lead to tendon rupture. Tendinitis and tendon rupture, sometimes bilateral, may occur
within 48 hours of starting treatment with levofloxacin and have been reported up to
several months after discontinuation of treatment. The risk of tendinitis and tendon
rupture is increased in patients aged over 60 years, in patients receiving daily doses of
1000 mg and in patients using corticosteroids. The daily dose should be adjusted in
elderly patients based on creatinine clearance (see section 4.2). Close monitoring of
these patients is therefore necessary if they are prescribed levofloxacin. All patients
should consult their physician if they experience symptoms of tendinitis. If tendinitis
is suspected, treatment with Levofloxacin Kabi must be halted immediately, and
appropriate treatment (e.g. immobilisation) must be initiated for the affected tendon
(see sections 4.3 and 4.8).
Clostridium difficile-associated disease
Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment
with Levofloxacin Kabi (including several weeks after treatment), , may be
symptomatic of Clostridium difficile-associated disease (CDAD). CDAD may range
in severity from mild to life threatening, the most severe form of which is
pseudomembranous colitis (see section 4.8). It is therefore important to consider this
diagnosis in patients who develop serious diarrhoea during or after treatment with
levofloxacin. If CDAD is suspected or confirmed, levofloxacin should be stopped
immediately and appropriate treatment initiated without delay. Anti-peristaltic
medicinal products are contraindicated in this clinical situation.

Patients predisposed to seizures
Quinolones may lower the seizure threshold and may trigger seizures. Levofloxacin is
contraindicated in patients with a history of epilepsy (see section 4.3) and, as with
other quinolones, should be used with extreme caution in patients predisposed to
seizures or or concomitant treatment with active substances that lower the cerebral
seizure threshold, such as theophylline (see section 4.5). In case of convulsive
seizures (see section 4.8), 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. Therefore, if levofloxacin has to be used in these patients, potential
occurrence of haemolysis should be monitored.
Patients with renal impairment
Since levofloxacin is excreted mainly by the kidneys, the dose of Levofloxacin Kabi
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.
Severe bullous reactions
Cases of severe bullous skin reactions such as Stevens-Johnson syndrome or toxic
epidermal necrolysis have been reported with levofloxacin (see section 4.8). Patients
should be advised to contact their doctor immediately prior to continuing treatment if
skin and/or mucosal reactions occur.
Dysglycaemia
As with all quinolones, disturbances in blood glucose, including both hypoglycaemia
and hyperglycaemia have been reported, usually in diabetic patients receiving
concomitant treatment with an oral hypoglycemic agent (e.g., glibenclamide) or with
insulin. Cases of hypoglycaemic coma have been reported. In diabetic patients,
careful monitoring of blood glucose is recommended. (See section 4.8).
Prevention of photosensitisation
Photosensitisationhas been reported with levofloxacin (see section 4.8). , It is
recommended that patients should not expose themselves unnecessarily to strong
sunlight or to artificial UV rays (e.g. sunray lamp, solarium), during treatment and for
48 hours following treatment discontinuation 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 levofloxacin 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 antiarrhythmic, tricyclic antidepressants, macrolides, antipsychotics ).
- uncorrected electrolyte imbalance (e.g. hypokalemia, hypomagnesemia)
- cardiac disease (e.g. heart failure, myocardial infarction, bradycardia)
Elderly patients and women may be more sensitive to QTc-prolonging medications.
Therefore, caution should be taken when using fluoroquinolones, including
levofloxacin, in these populations. (See section 4.2 Elderly, 4.5, 4.8 and 4.9).
Peripheral neuropathy
Peripheral sensory neuropathy and peripheral sensory motor neuropathy have been
reported in patients receiving fluoroquinolones, including levofloxacin, which can be
rapid in its onset (see section 4.8). Levofloxacin should be discontinued if the patient
experiences symptoms of neuropathy in order to prevent the development of an
irreversible condition.
Hepatobiliary disorders
Cases of hepatic necrosis up to fatal 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.
Exacerbation of myasthenia gravis
Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and
may exacerbate muscle weakness in patients with myasthenia gravis. Postmarketing
serious adverse reactions, including deaths and the requirement for respiratory
support, have been associated with fluoroquinolone use in patients with myasthenia
gravis. Levofloxacin is not recommended in patients with a known history of
myasthenia gravis.
Vision disorders
If vision becomes impaired or any effects on the eyes are experienced, an eye
specialist should be consulted immediately (see sections 4.7 and 4.8).
Superinfection
The use of levofloxacin, especially if prolonged, may result in overgrowth of nonsusceptible organisms. If superinfection occurs during therapy, appropriate measures
should be taken.
Interference with laboratory test
In patients treated with levofloxacin, determination of opiates in urine may give falsepositive results. It may be necessary to confirm positive opiate screens by more
specific method.
Levofloxacin may inhibit the growth of Mycobacterium tuberculosis and, therefore,
may give false-negative results in the bacteriological diagnosis of tuberculosis.

4.5.

Interaction with other medicinal products and other forms of interaction
Effect of other medicinal products on Levofloxacin Kabi
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 antiinflammatory 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
effect 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 Levofloxacin Kabi 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
antiarrhythmic, tricyclic antidepressants, macrolides, antipsychotics). (See section 4.4
QT interval prolongation).
Other relevant information

In a pharmacokinetic interaction study, levofloxacin did not affect the
pharmacokinetics of theophylline (which is a probe substrate for CYP1A2), indicating
that levofloxacin is not a CYP1A2 inhibitor.

4.6.

Fertility, pregnancy and lactation
Pregnancy
There are limited amount of data from the use of levofloxacin in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to
reproductive toxicity (see section 5.3).
However in the absence of human data and due to that experimental data suggest a
risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing
organism, Levofloxacin Kabi solution for infusion must not be used in pregnant
women (see sections 4.3 and 5.3).
Breast-feeding
Levofloxacin Kabi is contraindicated in breast-feeding women. There is insufficient
information on the excretion of levofloxacin in human milk; however other
fluoroquinolones are excreted in breast milk. In the absence of human data and due to
that experimental data suggest a risk of damage by fluoroquinolones to the weightbearing cartilage of the growing organism, Levofloxacin Kabi solution for infusion
must not be used in breast-feeding women (see sections 4.3 and 5.3).
Fertility
Levofloxacin caused no impairment of fertility or reproductive performance in rats.

4.7.

Effects on ability to drive and use machines
Some undesirable effects (e.g. dizziness/vertigo, drowsiness, 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).

4.8

Undesirable effects
The information given below is based on data from clinical studies in more than 8300
patients and on extensive post marketing experience.
Frequencies in this table are defined using the following convention: very common
(1/10), common (1/100, <1/10), uncommon (1/1000 , <1/100), rare (1/10000 to
<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.

Rare (≥1/10,000 to
<1/1,000)

Not known (cannot be
estimated from available
data)

Thrombocytopenia
Neutropenia

Pancytopenia
Agranulocytosis
Haemolytic anaemia

Angioedema
Hypersensitivity (see
section 4.4)

Anaphylactic shock a
Anaphylactoid shock a (see
section 4.4)

Anorexia

Hypoglycaemia
particularly in diabetic
patients (see section 4.4)

Hyperglycaemia
Hypoglycaemic coma

Insomnia

Anxiety
Confusional
state
Nervousness

Psychotic reactions (with
e.g. hallucination,
paranoia)
Depression
Agitation
Abnormal dreams
Nightmares

Psychotic disorders with
self-endangering behaviour
including suicidal ideation
or suicide attempt (see
section 4.4)

Nervous system Headache
disorders
Dizziness

Somnolence
Tremor
Dysgeusia

Convulsion (see sections Peripheral sensory
4.3 and 4.4)
neuropathy (see section
Paraesthesia
4.4)
Peripheral sensory motor
neuropathy (see section
4.4)
Parosmia including
anosmia
Dyskinesia
Extrapyramidal disorder
Ageusia
Syncope
Benign intracranial
hypertension

System organ
class

Common
(≥1/100 to
<1/10 )

Uncommon
(≥1/1,000 to
<1/100)

Infections and
infestations

Fungal
infection
including
Candida
infection
Pathogen
resistance

Blood and the
lymphatic
system
disorders

Leukopenia
Eosinophilia

Immune system
disorders

Metabolism and
nutrition
disorders

Psychiatric
disorders

Eye disorders

Visual disturbances such
as blurred vision (see
section 4.4)

Transient vision loss (see
section 4.4)

Ear and
Labyrinth
disorders

Vertigo

Cardiac
disorders

Vascular
disorders

Hearing loss
Hearing impaired

Tachycardia, Palpitation

Ventricular tachycardia,
which may result in cardiac
arrest
Ventricular arrhythmia and
torsade de pointes
(reported predominantly in
patients with risk factors of
QT prolongation),
electrocardiogram QT
prolonged (see sections 4.4
and 4.9)

Hypotension

Applies to iv
form only:
Phlebitis

Respiratory,
thoracic and
mediastinal
disorders

Tinnitus

Dyspnoea

Bronchospasm
Pneumonitis allergic

Gastrointestinal
disorders

Diarrhoea
Vomiting
Nausea

Abdominal
pain
Dyspepsia
Flatulence
Constipation

Diarrhoea – haemorrhagic
which in very rare cases
may be indicative of
enterocolitis, including
pseudomembranous colitis
(see section 4.4)
Pancreatitis

Hepatobiliary
disorders

Hepatic
enzyme
increased
(ALT/AST,
alkaline
phosphatase,
GGT)

Blood
bilirubin
increased

Jaundice and severe liver
injury, including fatal cases
with acute liver failure,
primarily in patients with
severe underlying diseases
(see section 4.4)
Hepatitis

Rash
Pruritus
Urticaria
Hyperhidrosis

Toxic epidermal necrolysis
Stevens-Johnson syndrome
Erythema multiforme
Photosensitivity reaction
(see section 4.4)
Leukocytoclastic vasculitis
Stomatitis

Skin and
subcutaneous
tissue disorders
b

Musculoskeletal
and connective
tissue disorders

Arthralgia
Myalgia

Tendon disorders (see
sections 4.3 and 4.4)
including tendinitis (e.g.
Achilles tendon)
Muscular weakness

Rhabdomyolysis
Tendon rupture (e.g.
Achilles tendon) (see
sections 4.3 and 4.4)
Ligament rupture

which may be of special
importance in patients
with myasthenia gravis
(see section 4.4)
Renal and
Urinary
disorders
General
disorders and
administration
site conditions

Blood
creatinine
increased
Asthenia
Applies to iv
form only:
Infusion site
reaction (pain,
reddening)

Muscle rupture
Arthritis

Renal failure acute (e.g.
due to interstitial
nephritis)
Pyrexia

Pain (including pain in
back, chest, and
extremities)

a Anaphylactic and anaphylactoid reactions may sometimes occur even after the first
dose.
b Mucocutaneous reactions may sometimes occur even after the first dose
Other undesirable effects which have been associated with fluoroquinolone
administration include:


attacks of porphyria in patients with porphyria

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9.

Overdose
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 Kabi solution for infusion are central nervous system
symptoms such as confusion, dizziness, impairment of consciousness, and convulsive
seizures, increases in QT interval.
CNS effects including confusional state, convulsion, hallucination, and tremor have
been observed in post marketing experience.
In the event of overdose, symptomatic treatment should be implemented. ECG
monitoring should be undertaken, because of the possibility of QT interval
prolongation. Haemodialysis, including peritoneal dialysis and CAPD, are not
effective in removing levofloxacin from the body. No specific antidote exists.

5.

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic properties
Pharmacotherapeutic group: quinolone antibacterials, fluoroquinolones, ATC-code:
J01MA12.
Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class and is the
S (-) enantiomer of the racemic active substance ofloxacin.
Mechanism of action
As a fluoroquinolone antibacterial agent, levofloxacin acts on the 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
Resistance to levofloxacin is acquired through a stepwise process by target site
mutations in both type II topoisomerases, DNA gyrase and topoisomerase IV. Other
resistance mechanisms such as permeation barriers (common in Pseudomonas
aeruginosa) and efflux mechanisms may also affect susceptibility to levofloxacin.
Cross-resistance between levofloxacin and other fluoroquinolones is observed. 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 (version 2.0, 2012-01-01):
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
2,3
H.influenzae
≤1 mg/L
>1 mg/L
M.catarrhalis 3
≤1 mg/L
>1 mg/L
Non-species related
≤1 mg/L
>2 mg/L
breakpoints4
1. The breakpoints for levofloxacin relate to high dose therapy.
2. Low-level fluoroquinolone resistance (ciprofloxacin MICs of 0.12-0.5 mg/l)
may occur but there is no evidence that this resistance is of clinical importance in
respiratory tract infections with H. influenzae.
3. Strains with MIC values above the susceptible 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 must be sent to a
reference laboratory. Until there is evidence regarding clinical response for

confirmed isolates with MIC above the current resistant breakpoint they should be
reported resistant.
4. Breakpoints apply to an oral dose of 500 mg x 1 to 500 mg x 2 and an
intravenous dose of 500 mg x 1 to 500 mg x 2.
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
Bacillus anthracis
Staphylococcus aureus methicillin-susceptible
Staphylococcus saprophyticus
Streptococci, group C and G
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes
Aerobic Gram- negative bacteria
Eikenella corrodens
Haemophilus influenzae
Haemophilus para-influenzae
Klebsiella oxytoca
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#
Coagulase negative Staphylococcus spp
Aerobic Gram- negative bacteria
Acinetobacter baumannii
Citrobacter freundii

Enterobacter aerogenes
Enterobacter agglomerans
Enterobacter cloacae
Escherichia coli
Klebsiella pneumoniae
Morganella morganii
Proteus mirabilis
Providencia stuartii
Pseudomonas aeruginosa
Serratia marcescens
Anaerobic bacteria
Bacteroides fragilis
Inherently Resistant Strains
Aerobic Gram-positive bacteria
Enterococcus faecium
#
Methicillin-resistant S. aureus are very likely to possess co-resistance to
fluoroquinolones, including levofloxacin.

5.2.

Pharmacokinetic properties
Absorption
Orally administered levofloxacin is rapidly and almost completely absorbed with peak
plasma concentrations being obtained within 1-2 h. The absolute bioavailability is 99100 %.
Food has little effect on the absorption of levofloxacin.
Steady state conditions are reached within 48 hours following a 500 mg once or twice
daily dosage regimen.
Distribution
Approximately 30 - 40 % of levofloxacin is bound to serum protein.
The mean volume of distribution of levofloxacin is approximately 100 l after single
and repeated 500 mg doses, indicating widespread distribution into body tissues.
Penetration into tissues and body fluids:
Levofloxacin has been shown to penetrate into bronchial mucosa, epithelial lining
fluid, alveolar macrophages, lung tissue, skin (blister fluid), prostatic tissue and urine.
However, levofloxacin has poor penetration intro cerebro-spinal fluid.
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 stereochemically 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).
The mean apparent total body clearance of levofloxacin following a 500 mg single
dose was 175 +/-29.2 ml/min.
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 1000 mg.
Special populations
Subjects with renal insufficiency
The pharmacokinetics of levofloxacin are 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:
Pharmacokinetics in renal insufficiency following single oral 500 mg dose
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 kinetics 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.

5.3.

Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies
of single dose toxicity, repeated dose toxicity, carcinogenic potential and toxicity to
reproduction and development.
Levofloxacin caused no impairment of fertility or reproductive performance in rats
and its only effect on fetuses was delayed maturation as a result of maternal toxicity.
Levofloxacin did not induce gene mutations in bacterial or mammalian cells but did
induce chromosome aberrations in Chinese hamster lung cells in vitro. These effects
can be attributed to inhibition of topoisomerase II. In vivo tests (micronucleus, sister
chromatid exchange, unscheduled DNA synthesis, dominant lethal tests) did not show
any genotoxic potential.

Studies in the mouse 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 photocarcinogenity
study.
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.

6.

PHARMACEUTICAL PARTICULARS

6.1.

List of excipients
Sodium chloride
Sodium hydroxide (for pH-adjustmen),
Hydrochloric acid (for pH-adjustment)
Water for injection.

6.2

Incompatibilities
Levofloxacin Kabi 5 mg/ml solution for infusion should not be mixed with heparin or
alkaline solutions (e.g. sodium hydrogen carbonate).
This medicinal product must not be mixed with other medicinal products except those
mentioned in section 6.6.

6.3

Shelf life
Solution for infusion packed for sale:
Bottlepack 50 ml and 100 ml: 3 years
freeflex® bags 50 ml: 18 months
freeflex® bags 100 ml: 2 years
Diluted solution:
Dilution is not necessary prior to administration.
For the diluted product chemical and physical in use stability has been demonstrated
for 3 hours at 25 °C.
After first opening:

From the microbiological point of view, the product should be used immediately
(within 3 hours). If not used immediately (within 3 hours), in-use storage times and
conditions prior to use are the responsibility of the user, unless reconstitution/dilution
has be taken place in controlled and validated conditions.
No protection from light is necessary during infusion.

6.4 Special precautions for storage
Bottle pack (KabiPac®):
Keep container in the outer carton in order to protect from light.
Do not refrigerate or freeze.
freeflex® bags:
Do not store above 25°C.
Keep container in the outer carton in order to protect from light.
Do not refrigerate or freeze.
For storage conditions of the diluted product see section 6.3

6.5.

Nature and contents of container
50 ml filled in 100 ml bottle: Low-density polyethylene container (bottlepack) of 100
ml, closed with a cap containing a rubber disc.
Pack sizes: 1, 10 and 25 bottles
50 ml filled in 100 ml bag: 100 ml polyolefine Freeflex bag system
Pack size: 10 and 20 bags
100 ml filled in 100 ml bottle: Low-density polyethylene container (bottlepack) of
100 ml, closed with a cap containing a rubber disc.
Pack sizes: 1, 10 and 25 bottles.
100 ml filled in 100 ml bag: 100 ml polyolefine Freeflex bag system
Pack size: 10 and 20 bags
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.

Mixture with other solutions for infusion:

Levofloxacin solution for infusion is compatible with the following solutions for
infusion:
- Glucose 50 mg/ml (5%).
- Glucose-Ringer 25mg/ml (2.5%).
- Sodium chloride 9mg/ml (0.9%).
- Amino acid solution
See section 6.2 for incompatibilities.

7

MARKETING AUTHORISATION HOLDER

Fresenius Kabi Limited
Cestrian Court
Eastgate Way
Manor Park
Runcorn
Cheshire
WA7 1NT
UK

8

MARKETING AUTHORISATION NUMBER(S)

PL 08828/0208

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
20/07/2009
Last renewal date: 30/01/2014

10

DATE OF REVISION OF THE TEXT
30/01/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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