LEVOFLOXACIN KABI 5 MG / ML SOLUTION FOR INFUSION - summary of medicine 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

4.1. Therapeutic indications

Levofloxacin 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 / Complicated skin and skin structure infections.

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

Acute 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)

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 000 ml/min)

1No 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:

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.

4.4. Special warnings and precautions for use

The use of levofloxacin should be avoided in patients who have experienced serious adverse reactions in the past when using quinolone or fluoroquinolone containing products (see section 4.8). Treatment of these patients with levofloxacin should only be initiated in the absence of alternative treatment options and after careful benefit/risk assessment (see also section 4.3).

Aortic aneurysm and dissection, and heart valve regurgitation/in­competence

Epidemiologic studies report an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and of aortic and mitral valve regurgitation after intake of fluoroquinolones. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/in­competence of any of the heart valves have been reported in patients receiving fluoroquinolones (see section 4.8).

Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease or congenital heart valve disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection or heart valve disease, or in presence of other risk factors or conditions predisposing

– for both aortic aneurysm and dissection and heart valve regurgitation/in­competence (e.g. connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behcet’s disease, hypertension, rheumatoid arthritis) or additionally

– for aortic aneurysm and dissection (e.g. vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjogren’s syndrome) or additionally

– for heart valve regurgitation/in­competence (e.g. infective endocarditis).

The risk of aortic aneurysm and dissection, and their rupture may also be increased in patients treated concurrently with systemic corticosteroids.

In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.

Patients should be advised to seek immediate medical attention in case of acute dyspnoea, new onset of heart palpitations, or development of oedema of the abdomen or lower extremities.

Risks of resistance

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

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 177 mg sodium per 50 ml, equivalent to 8.85 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Prolonged, disabling and potentially irreversible serious adverse drug reactions

Very rare cases of prolonged (continuing months or years), disabling and potentially irreversible serious adverse drug reactions affecting different, sometimes multiple, body systems (musculoskeletal, nervous, psychiatric and senses) have been reported in patients receiving quinolones and fluoroquinolones irrespective of their age and pre-existing risk factors. Levofloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction and patients should be advised to contact their prescriber for advice.

Tendinitis and tendon rupture

Tendinitis and tendon rupture (especially but not limited to Achilles tendon), sometimes bilateral, may occur as early as within 48 hours of starting treatment with quinolones and fluoroquinolones and have been reported to occur even up to several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in patients receiving daily doses of 1,000 mg levofloxacin in older patients, patients with renal impairment, patients with solid organ transplants, and those treated concurrently with corticosteroids. Therefore, concomitant use of corticosteroids should be avoided.

At the first sign of tendinitis (e.g. painful swelling, inflammation the treatment should be discontinued and alternative treatment should be considered. The affected limb(s) should be appropriately treated (e.g. immobilisation). Corticosteroids should not be used if signs of tendinopathy occur.

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. Antiperistaltic 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 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 cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN: also known as Lyell's syndrome), Stevens Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS), which could be life-threatening or fatal, have been reported with levofloxacin (see section 4.8). At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions, and be closely monitored. If signs and symptoms suggestive of these reactions appear, levofloxacin should be discontinued immediately and an alternative treatment should be considered. If the patient has developed a serious reaction such as SJS, TEN or DRESS with the use of levofloxacin, treatment with levofloxacin must not be restarted in this patient at any time.

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

Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesia, hypaesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. Patients under treatment with levofloxacin should be advised to inform their doctor prior to continuing treatment if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop in order to prevent the development of potentially irreversible condition. (see section 4.8) 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 non-susceptible 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 false-positive 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 is a 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 as experimental data suggests a risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, Levofloxacin solution for infusion must not be used in pregnant women (see sections 4.3 and 5.3).

Breast-feeding

Levofloxacin 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 as experimental data suggests a risk of damage by fluoroquinolones to the weightbearing cartilage of the growing organism, Levofloxacin 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.

a

Anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose. b

Mucocutaneous reactions may sometimes occur even after the first dose

* Very rare cases of prolonged (up to months or years), disabling and potentially irreversible serious drug reactions affecting several, sometimes multiple, system organ classes and senses (including reactions such as tendonitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathies associated with paraesthesia, depression, fatigue, memory impairment, sleep disorders, and impairment of hearing, vision, taste and smell) have been reported in association with the use of quinolones and fluoroquinolones in some cases irrespective of pre-existing risk factors (see section 4.4).

* * Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal ones), and of regurgitation/in­competence of any of the heart valves have been reported in patients receiving fluoroquinolones (see section 4.4).

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:

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

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):

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 (t/2: 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

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

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:

KabiPac bottles 50 ml and 100 ml: 3 years

freeflex ® bags 50 ml: 18 months freeflex® bags 100 ml: 2 years

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.

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 storageKabiPac bottles:

Keep container in the outer carton in order to protect from light.

Do not refrigerate or freeze.

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 (KabiPac) of 100 ml, closed with a cap containing a rubber disc

Pack sizes: 1, 10, 20 and 25 bottles

50 ml filled in 100 ml bag: 100 ml polyolefin Freeflex bag system

Pack size: 10 and 20 bags

100 ml filled in 100 ml bottle: Low-density polyethylene container (KabiPac) of 100 ml, closed with a cap containing a rubber disc

Pack sizes: 1, 10, 20 and 25 bottles

100 ml filled in 100 ml bag: 100 ml polyolefin 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 THEAUTHORISATION

20/07/2009

Last renewal date: 30/01/2014