Levofloxacin 5 Mg/Ml Solution For Infusion

Document: spc-doc_PL 24598-0024 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Levofloxacin 5 mg/ml solution for infusion.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 100 ml polypropylene bottle contains 500 mg of levofloxacin as levofloxacin hemihydrate.

One ml of solution for infusion contains 5 mg of levofloxacin.

Each 100 ml of solution for infusion contains 15.4 mmol (354.2 mg) Sodium (as chloride).

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for infusion.

Clear greenish-yellow solution.

The osmolality of the solution for infusion is approximately 300 mOsm/kg.

The pH of the solution for infusion is approximately 4.8.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

In adults for whom intravenous therapy is considered to be appropriate, levofloxacin solution for infusion is indicated for the treatment of the following infections when due to levofloxacin-susceptible microorganisms:

• Community-acquired pneumonia (when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of this infection).

• Complicated urinary tract infections including pyelonephritis.

• Chronic bacterial prostatitis.

Skin and soft tissue infections (see section 4.4).

Before prescribing levofloxacin, consideration should be given to national and/or local guidance on the appropriate use of fluoroquinolones.

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 sensitivity of the presumed causative pathogen. It is usually possible to switch from initial intravenous treatment to the oral route after a few days (Levofloxacin 250 or 500 mg tablets), according to the condition of the patient. Given the bioequivalence of the parenteral and oral forms, the same dosage can be used.

Duration of treatment

The duration of treatment varies according to the course of the disease. As with antibiotic therapy in general, administration of levofloxacin c (solution for infusion or 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

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). It is possible to switch from an initial intravenous application to the oral route at the same dosage after a few days, according to the condition of the patient.

For incompatibilities see section 6.2 and compatibility with other infusion solutions see section 6.6.

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)

Community-acquired

pneumonia

500 mg once or twice daily

Complicated urinary tract infections including

250 mg¹ once daily

pyelonephritis
Chronic bacterial prostatitis.	500mg once daily
Skin and soft tissue infections	500 mg twice daily

'Consideration should be given to increasing the dose in cases of severe infection.

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
< '0 ml/min (including haemodialysis and CAPD)¹	then: 125 mg/48 h	then: '25 mg/24 h	then: 125 mg/24 h

'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

Levofloxacin is contraindicated in children and growing adolescents (see section 4.3).

4.3 Contraindications

Levofloxacin solution for infusion must not be used:

• in patients hypersensitive to levofloxacin or any other quinolone and 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

4.4 Special warnings and precautions for use

In the most severe cases of pneumococcal pneumonia Levofloxacin may not be the optimal therapy.

Nosocomial infections due to P. aeruginosa may require combination therapy. Infusion Time

The recommended infusion time of at least 30 minutes for 250 mg or 60 minutes for 500mg Levofloxacin 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.

Methicillin-resistant Stqphylococcus aureus (MRSA)

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 (see section 5.1).

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 Levofloxacin. All patients should consult their physician if they experience symptoms of tendinitis. If tendinitis is suspected, treatment with Levofloxacin 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 Levofloxacin solution for infusion, may be symptomatic of Clostridium difficile-associated disease, the most severe form of which is pseudomembranous colitis. If pseudomembranous colitis is suspected, Levofloxacin solution for infusion 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

Levofloxacin solution for infusion is 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 antiinflammatory 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 Levofloxacin 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 Levofloxacin in combination with a vitamin K antagonist (e.g. warfarin), coagulation tests should be monitored when these drugs are given concomittantly (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 self-endangering 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.

Cardiac disorders

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 anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics)

• uncorrected electrolyte imbalance (e.g. hypokalaemia, hypomagnesaemia)

• 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, 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 falsepositive 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.

This medicinal product contains 15.4 mmol (354.2 mg) Sodium per 100ml solution. This should be taken into account in patients on a controlled sodium diet and in cases where fluid restriction is required.

4.5 Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on Levofloxacin

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 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 Levofloxacin 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 anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see section 4.4).

4.6 Fertility, Pregnancy and lactation

Fertility

Animal studies indicate that levofloxacin has no effect on fertility

Pregnancy

There are no data with respect to 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). In juvenile and prenatal animals exposed to quinolones, effects on immature cartilage have been observed; thus, it cannot be excluded that the drug could cause damage to articular cartilage in the human immature organism / fetus (see section 5.3). The product is therefore contraindicated during pregnancy.

Lactation

There is insufficient information with respect to the excretion of levofloxacin in human and/or animal milk. In the absence of these data and given the potential risk of articular damage, levofloxacin is contraindicated during breast-feeding.

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, £ 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.

System organ class

Common

(>1/100 to <1/10 )

Uncommon

£1/1,000 to <1/100)

Rare £1/10,000 to <1/1,000)

Not known (cannot be estimated from available data)

Infections and infestations

Fungal

infection

including

Candida

infection

Pathogen

resistance

Blood and lymphatic system disorders

Leukopenia,

eosinophilia

Thrombocytopenia,

neutropenia

Pancytopenia,

Agranulocytosis,

haemolytic

anaemia

Immune system disorders			Angioedema Hypersensitivity (see section 4.4)	Anaphylactic shock a Anaphylactoid shock ^a (see section 4.4)
Metabolism and nutrition disorders		Anorexia	Hypoglycaemia particularly in diabetic patients (see section 4.4)	Hyperglycaemia Hypoglycaemic coma (see section 4.4)
Psychiatric disorders	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 disorders	Headache Dizziness	Somnolence Tremor Dysgeusia	Convulsion (see sections 4.3 and 4.4) Paraesthesia	Peripheral sensory neuropathy (see section 4.4) Peripheral sensory motor neuropathy (see section 4.4) Parosmia including anosmia Dyskinesia Extrapyramidal disorder Ageusia Syncope Benign intracranial hypertension
Eye disorders			Visual disturbances such as blurred vision (see section 4.4)	Transient vision loss (see section 4.4)
Ear and Labyrinth disorders		Vertigo	Tinnitus	Hearing loss Hearing impaired
Cardiac			Tachycardia,	Ventricular

disorders			Palpitation	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)
Vascular	Applies to iv		Hypotension
disorders	form only:
	Phlebitis
Respiratory, thoracic and		Dyspnoea		Bronchospasm
mediastinal				Pneumonitis
disorders				allergic
Gastro-intestinal	Diarrhoea	Abdominal		Diarrhoea -
disorders	Vomiting	pain		haemorrhagic which in very rare
		Dyspepsia		cases may be
	Nausea	Flatulence Constipation		indicative of enterocolitis, including pseudomembranous colitis (see section 4.4)
	Nausea
				Pancreatitis
Hepatobiliary	Hepatic	Blood		Jaundice and severe
disorders	enzyme	bilirubin		liver injury,
	increased	increased		including fatal
	(ALT/AST,			cases with acute
	alkaline			liver failure,
	phosphatase,			primarily in
	GGT)			patients with severe underlying diseases (see section 4.4)
				Hepatitis
Skin and		Rash		Toxic epidermal
subcutaneous tissue disorders		Pruritus		necrolysis
b				Stevens-Johnson

		Urticaria Hyperhidrosis		syndrome Erythema multiforme Photosensitivity reaction (see section 4.4) Leukocytoclastic vasculitis Stomatitis
Musculoskeletal and connective tissue disorders		Arthralgia Myalgia	Tendon disorders (see sections 4.3 and 4.4) including tendinitis (e.g. Achilles tendon) Muscular weakness which may be of special importance in patients with myasthenia gravis (see section 4.4)	Rhabdomyolysis Tendon rupture (e.g. Achilles tendon) (see sections 4.3 and 4.4) Ligament rupture Muscle rupture Arthritis
Renal and Urinary disorders		Blood creatinine increased	Renal failure acute (e.g. due to interstitial nephritis)
General disorders and administration site conditions	Applies to iv form only: Infusion site reaction (pain, reddening)	Asthenia	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

For UK: Yellow Card Scheme, Website: (www.mhra.gov.uk/yellowcard).

For IE: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www. hpra.ie, E-mail: medsafety@hpra.ie.

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 solution for infusion are central nervous system symptoms such as confusion, dizziness, impairment of consciousness, and convulsive seizures, increases in QT interval.

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 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 cross-resistance 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:

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.catarrhalis ¹	^ 1 mg/L	>1 mg/L
Non-species related breakpoints²	^ 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.

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

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 *

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.

5.2 Pharmacokinetic properties

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 po were 8.3 pg/g and 10.8 pg/ml respectively. These were reached approximately one hour after administration.

Penetration into Lung Tissue

Maximum levofloxacin concentrations in lung tissue after 500 mg po were approximately 11.3 pg/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 pg/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 pg/g, 8.2 pg/g and 2.0 pg/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 desmethyl-levofloxacin 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 (t./₂: 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 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:

Cl_cr [ml/min]	< 20	20 - 40	50 - 80
Cl_R [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.

5.3 Preclinical safety data

Acute toxicity

The median lethal dose (LD₅₀) values obtained in mice and rats after intravenous administration of levofloxacin were in the range 250-400 mg/kg; in dogs the LD₅₀value was approximately 200 mg/kg with one of two animals which received this dose dying.

Repeated dose toxicity

During repeat-dose (1 month) intravenous studies, common observations included reduced food consumption and minor alterations in haematological and biochemical parameters at 180 mg/kg/day in the rat and a minor reduction in food and water consumption at 63 mg/kg/day in the monkey.

Reproductive toxicity

Levofloxacin had no effect on fertility or reproductive performance and was not teratogenic in the rat. In the rabbit, levofloxacin had no effect on fertility, was not teratogenic and its only effect on fetuses was delayed maturation at doses resulting in maternal toxicity.

Genotoxicity & Carcinogenic potential

Levofloxacin induced chromosome aberrations in Chinese hamster lung cells in vitro at or above 100 pg/ml, in the absence of metabolic activation. However, levofloxacin did not show any genotoxic potential in a series of other in vitro and in vivo tests and no indication of carcinogenic potential was observed.

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.

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.

In immature dogs (4-5 months old), oral doses of 10 mg/kg/day for 7 days and intravenous doses of 4 mg/kg/day for 14 days of levofloxacin resulted in arthropathic lesions. Administration at oral doses of 300 mg/kg/day for 7 days and intravenous doses of 60 mg/kg/day for 4 weeks produced arthropathy in juvenile rats. Three-month old beagle dogs dosed orally with levofloxacin at 40 mg/kg/day exhibited clinically severe arthrotoxicity resulting in the termination of dosing at Day 8 of a 14-day dosing routine. Slight musculoskeletal clinical effects, in the absence of gross pathological or histopathological effects, resulted from the lowest dose level of 2.5 mg/kg/day (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 (approximately 0.7-fold and 2.4-fold the pediatric dose, respectively, based on AUC comparisons). Articular cartilage gross pathology and histopathology persisted to the end of the 18-week recovery period for those dogs from the 10 and 40 mg/kg/day dose levels.

6.1 List of excipients

Sodium chloride

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injection

(Na + concentration: 154 mmol / L).

6.2 Incompatibilities

Levofloxacin 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

3 years.

Shelf life after removal of the outer pouch or individual carton box: To be used immediately after removing from the pouch or individual carton box.

Dilution is not necessary prior to administration.

For the diluted product chemical and physical in use stability has been demonstrated for 2 hours at 25^oC.

From a microbiological point of view, the solution for infusion should be used immediately once opened. If not used immediately, in-use storage times and conditions are the responsibility of the user, unless reconstitution/dilution has taken place in controlled and validated conditions.

6.4 Special precautions for storage

Keep the bottle in the outer pouch or individual carton box in order to protect from light (see section 6.3). Inspect visually prior to use. Only clear solutions without particles should be used.

6.5 Nature and contents of container

100ml, plastic bottles of polypropylene, with a molded plastic cap, a rubber (type II) gasket and a pull ring. Each bottle is placed in a metalized plastic pouch. Packs of 10 bottles are available.

100ml, plastic bottles of polypropylene, with a molded plastic cap, a rubber (type II) gasket and a pull ring. Each bottle is placed in a carton box. 100ml bottle comes in a box of 1.

6.6 Special precautions for disposal

Levofloxacin 5 mg/ml solution for infusion should be used immediately after perforation of the rubber stopper in order to prevent any bacterial contamination. No protection from light is necessary during infusion.

As for all medicines, any unused medicinal product should be disposed of accordingly and in compliance with local environmental regulations.

For single use only.

Mixture with other solutions for infusion:

Levofloxacin solution for infusion is compatible with the following solutions for infusion when diluted at a range of concentrations (0.5-4mg/ml):

• 0.9 % (9 mg/ml) sodium chloride solution.

• 5% (50 mg/ml) dextrose injection.

• 2.5 % (25 mg/ml) dextrose in Ringer solution.

Combination solutions for parenteral nutrition (amino acids, carbohydrates, electrolytes).

Levofloxacin solution for infusion may be given alone or with one of the above mentioned infusions.

See section 6.2 for incompatibilities.

7 MARKETING AUTHORISATION HOLDER

Noridem Enterprises Ltd. Evagorou & Makariou Mitsi Building 3 Suit. 115, 1065 Nicosia

Cyprus

8 MARKETING AUTHORISATION NUMBER(S)

PL 24598/0024

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29/03/2012

10 DATE OF REVISION OF THE TEXT

31/03/2015

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.

Non-species related breakpoints have been determined mainly on the basis of 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)