1. Name Of The Medicinal Product
Levofloxacin 5 mg/ml Solution for Infusion
2. Qualitative And Quantitative Composition
50 ml of solution for infusion contains 250 mg of levofloxacin as levofloxacin hemihydrate.
100 ml of solution for infusion contains 500 mg of levofloxacin as levofloxacin hemihydrate.
Contains 7.7 mmol (177 mg) sodium per 50 ml of solution for infusion.
Contains 15.4 mmol (354 mg) sodium per 100 ml of solution for infusion.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Solution for Infusion.
A clear greenish-yellow solution with pH of 3.8 to 5.8 and osmolarity of 302 mOsm/litre.
4. Clinical Particulars
4.1 Therapeutic Indications
In adults for whom intravenous therapy is considered to be appropriate, levofloxacin 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
Consideration should be given to national and/or local guidance on the appropriate use of fluoroquinolones
4.2 Posology And Method Of Administration
Levofloxacin is for intravenous use only.
Levofloxacin solution is administered by slow intravenous infusion once or twice daily. The dosage depends in the type and severity of the infection and the sensitivity of the presumed causative pathogen.
Duration of treatment:
The duration of therapy varies according to the course of the disease. Administration of levofloxacin 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 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 (see section 4.4 ).
For incompatibilities see 6.2 and compatibility with other infusion solutions see 6.6.
The following dose recommendations can be given for levofloxacin:
Special populations:
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 pyelonephritis
|
250 mg1 once daily
|
Chronic bacterial prostatitis
|
500 mg once daily
|
Skin and soft tissue infections
|
500 mg twice daily
|
1Consideration should be given to increasing the dose in cases of severe infection.
Dosage in patients with impaired renal function (creatinine clearance
|
Dose regimen
|
|
|
250 mg/24 h
|
500 mg/24 h
|
500 mg/12 h
|
|
Creatinine clearance
|
first dose: 250 mg
|
first dose: 500 mg
|
first dose: 500 mg
|
50 - 20 ml/min
|
then: 125 mg/24 h
|
then: 250 mg/24 h
|
then : 250 mg/12 h
|
19-10 ml/min
|
then: 125 mg/48 h
|
then: 125 mg/24 h
|
then: 125 mg/12 h
|
< 10 ml/min
(including haemodialysis and CAPD) 1
|
then: 125 mg/48 h
|
then: 125 mg/24 h
|
then: 125 mg/24 h
|
1No additional doses are required after haemodialysis or continuous ambulatory peritoneal dialysis (CAPD).
Dosage in patients with 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.
Dosage in elderly
No adjustment of dosage is required in the elderly, other than that imposed by consideration of renal function.
Dosage in children and adolescents
Levofloxacin is contraindicated in children and growing adolescents (see section 4.3).
4.3 Contraindications
Levofloxacin 5 mg/ml Solution for Infusion must not be used:
• in patients hypersensitive to levofloxacin, to any other quinolones or to 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.
This medicinal product contains 15.4 mmol (354 mg) sodium per 100 ml dose and 7.7 mmol (177 mg) sodium per 50 ml dose. To be taken into consideration by patients on a controlled sodium diet.
Infusion Time
The recommended infusion time of at least 30 minutes for 250 mg or 60 minutes for 500 mg levofloxacin 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.
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 including inhalation. 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 , may be symptomatic of Clostridium difficile-associated disease, the most severe form of which is pseudomembranous colitis. If pseudomembranous colitis is suspected, levofloxacin 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 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 anti-inflammatory drugs or with drugs which lower the cerebral seizure threshold, such as theophylline (see section 4.5). In case of convulsive seizures, treatment with levofloxacin should be discontinued.
Patients with G-6- phosphate dehydrogenase deficiency
Patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity may be prone to haemolytic reactions when treated with quinolone antibacterial agents, and so levofloxacin should be used with caution.
Patients with renal impairment
Since levofloxacin is excreted mainly by the kidneys, the dose should be adjusted in patients with renal impairment.
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, hypoglycaemia has been reported, usually in diabetic patents receiving concomitant treatment with an oral hypoglycaemic agent (e.g., glibenclamide) or with insulin. In these diabetic patients, careful monitoring e.g. 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 ultraviolet (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 prothrombin time/international normalised ratio (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 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. ClassIA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics)
- uncorrected electrolyte imbalance (e.g hypokalaemia, hypomagnesaemia)
- elderly
- cardiac disease (e.g. heart failure, myocardial infarction, bradycardia)
(See section 4.2 Elderly, section 4.5, section 4.8, section 4.9).
Peripheral neuropathy
Sensory or sensorimotor peripheral neuropathy has been reported in patients receiving fluoroquinolones, including levofloxacin, which can be rapid in its onset. Levofloxacin should be discontinued if the patient experiences symptoms of neuropathy in order to prevent the development of an irreversible condition.
Opiates
In patients treated with levofloxacin, determination of opiates in urine may give false-positive results. It may be necessary to confirm positive opiate screens by more specific method.
Hepatobiliary disorders
Cases of hepatic necrosis up to life threatening hepatic failure have been reported with levofloxacin, primarily in patients with severe underlying diseases, e.g. sepsis (see section 4.8). Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop such as anorexia, jaundice, dark urine, pruritus or tender abdomen.
Myasthenia
Levofloxacin should be used carefully in patients with myasthenia.
Methicillin resistant Staphylococcus aureus (MRSA)
Levofloxacin is not recommended for the treatment of MRSA infection. In case of a suspected or confirmed infection due to MRSA, treatment with an appropriate antibacterial agent should be started.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Iron salts, zinc, strontium, magnesium- or aluminium-containing antacids
Levofloxacin absorption is significantly reduced when iron salts, zinc, strontium or magnesium- or aluminium-containing antacids are administered concomitantly. It is recommended that preparations containing divalent or trivalent cations such as iron salts, or magnesium- or aluminium-containing antacids should not be taken 2 hours before or after levofloxacin administration (see section 4.2). No interaction has been found with calcium carbonate.
Sucralfate
The bioavailability of levofloxacin is significantly reduced when administered together with sucralfate. If the patient is to receive both sucralfate and levofloxacin, it is best to administer sucralfate 2 hours after the levofloxacin administration (see section 4.2).
Theophylline, fenbufen or similar non-steroidal anti-inflammatory drugs
No pharmacokinetic interactions of levofloxacin were found with theophylline in a clinical study. However a pronounced lowering of the cerebral seizure threshold may occur when quinolones are given concurrently with theophylline, non-steroidal anti-inflammatory drugs, or other agents which lower the seizure threshold.
Levofloxacin concentrations were about 13% higher in the presence of fenbufen than when administered alone.
Probenecid and cimetidine
Probenecid and cimetidine had a statistically significant effect on the elimination of levofloxacin. The renal clearance of levofloxacin was reduced by cimetidine (24%) and probenecid (34%). This is because both drugs are capable of blocking the renal tubular secretion of levofloxacin. However, at the tested doses in the study, the statistically significant kinetic differences are unlikely to be of clinical relevance.
Caution should be exercised when levofloxacin is coadministered with drugs that effect the tubular renal secretion such as probenecid and cimetidine, especially in renally impaired patients.
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.
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. ClassIA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics). (See section 4.4 QT interval prolongation).
Other relevant information
Clinical pharmacology studies were carried out to investigate possible pharmacokinetic interactions between levofloxacin and commonly prescribed drugs. 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.
4.6 Pregnancy And Lactation
Pregnancy
There is no information on the use of levofloxacin in pregnant women. Reproductive studies in animals did not raise specific concern. However in the absence of human data and due to the experimental risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism levofloxacin must not be used during pregnancy (see sections 4.3 and 5.3). Women of childbearing age receiving levofloxacin should be advised to avoid becoming pregnant, and to inform the treating physician immediately should this occur.
Lactation
There is evidence of excretion of fluoroquinolones in human breast milk. Due to this and to the experimental risk of damage to the weight-bearing cartilage of the growing organism, levofloxacin must not be used in breast-feeding women (see sections 4.3 and 5.3).
4.7 Effects On Ability To Drive And Use Machines
Levofloxacin has influence on the 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 5000 patients and on extensive post marketing experience.
The adverse reactions are described according to the MedRA organ class in the table below.
The following frequency rating has been used:
|
|
Very common:
|
|
Common:
|
|
Uncommon:
|
|
Rare:
|
|
Very rare:
|
< 1/10000
|
Not known:
|
Cannot be estimated from the available data
|
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Infections and infestations
Uncommon:
|
Fungal infection (and proliferation of other resistant microorganisms)
|
Blood and lymphatic system disorders
Common:
|
Nausea, diarrhoea
|
Uncommon:
|
Leukopenia, eosinophilia
|
Rare:
|
Thrombocytopenia, neutropenia
|
Very rare:
|
Agranulocytosis
|
Not Known:
|
Pancytopenia, haemolytic anaemia
|
Immune system disorders
Very rare:
|
Anaphylactic shock (see section 4.4)
Anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose
|
Not known:
|
Hypersensitivity (see section 4.4)
|
Metabolism and nutrition disorders
Uncommon:
|
Hypoglycemia, particularly in diabetic patients (see section 4.4)
|
Psychiatric disorders
Uncommon:
|
Insomnia, nervousness
|
Rare:
|
Psychotic disorder, depression, confusional state, agitation, anxiety
|
Very rare:
|
Psychotic reactions with self-endangering behaviour including suicidal ideation or acts (see section 4.4), hallucination
|
Nervous system disorders
Uncommon:
|
Dizziness, headache, somnolence
|
Rare:
|
Convulsion, tremor, paraesthesia
|
Very rare:
|
Sensory or sensorimotor peripheral neuropathy, dysgeusia including ageusia, parosmia including anosmia
|
Eye disorders
Very rare:
|
Visual disturbance
|
Ear and labyrinth disorders
Uncommon:
|
Vertigo
|
Very rare:
|
Hearing impaired
|
Not known:
|
Tinnitus
|
Cardiac disorders
Rare:
|
Tachcardia
|
Not known:
|
Ventricular arrhythmia and torsades de pointes (reported predominantly in patients with risk factors for QT prolongation), Electrocardiogram (ECG) QT prolonged (see section 4.4 QT interval prolongation and section 4.9)
|
Vascular disorders
Common:
|
Phlebitis
|
Rare:
|
Hypotension
|
Respiratory, thoracic and mediastinal disorders
Rare:
|
Bronchospasm, dyspnoea
|
Very rare:
|
Pneumonitis allergic
|
Gastrointestinal disorders
Common:
|
Diarrhoea, nausea
|
Uncommon:
|
Vomiting, abdominal pain, dyspepsia, flatulence, constipation
|
Rare:
|
Diarrhoea – haemorrhagic which in very rare cases may be indicative of enterocolitis, including pseudomembranous colitis
|
Hepatobiliary disorders
Common:
|
Hepatic enzyme increased (ALT/AST, alkaline phosphatise, GGT)
|
Uncommon:
|
Blood bilirubin increased
|
Very rare:
|
Hepatitis
|
Not known:
|
Jaundice and severe liver injury, including cases with acute liver failure, have been reported with levofloxacin, primarily in patients with severe underlying diseases (see section 4.4)
|
Skin and subcutaneous tissue disorders
Uncommon:
|
Rash, pruritis
|
Rare:
|
Urticaria
|
Very rare:
|
Angioneurotic oedema, photosensitivity reaction
|
Not known:
|
Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, hyperhidrosis
Mucocutaneous reactions may sometimes occur even after the first dose
|
Musculoskeletal and connective tissue disorders
Rare:
|
Tendon disorder (see section 4.4) including tendinitis (e.g. Achilles tendon), arthralgia, myalgia
|
Very rare
|
Tendon rupture (see section 4.4). This undesirable effect may occur within 48 hours of starting treatment and may be bilateral, muscular weakness which may be of special importance in patients with myasthenia gravis
|
Not known
|
Rhabdomyolysis
|
Renal and urinary disorders
Uncommon:
|
Blood creatinine increased
|
Very rare:
|
Renal failure acute (e.g. due to nephritis interstitial)
|
General disorders and administration site conditions
Common:
|
Infusion site reaction
|
Uncommon:
|
Asthenia
|
Very rare:
|
Pyrexia
|
Not known:
|
Pain (including pain in back, chest, and extremities)
|
Other undesirable effects which have been associated with fluoroquinolone administration include:
• extrapyramidal symptoms and other disorders of muscular coordination,
• hypersensitivity vasculitis,
• attacks of porphyria in patients with porphyria.
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 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. Electrocardiogram (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:
|
Anti-infectives for systemic use - Antibacterials for systemic use - 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 (2009-04-07):
Pathogen
|
Susceptible
|
Resistant
|
Enterobacteriaceae
|
|
>2 mg/L
|
Pseudomonas spp.
|
|
>2 mg/L
|
Acinetobacter spp.
|
|
>2 mg/L
|
Staphylococcus spp.
|
|
>2 mg/L
|
Streptococcus A,B,C,G
|
|
>2 mg/L
|
S. pneumoniae 1
|
|
>2 mg/L
|
H. influenzae
M. catarrhalis2
|
|
>1 mg/L
|
Non-species related breakpoints3
|
|
>2 mg/L
|
1 The S/I-breakpoint was increased from 1.0 to 2.0 to avoid dividing the wild type MIC distribution. The breakpoints relate to high dose therapy.
2 Strains with MIC values above the S/I breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate sent to a reference laboratory.
3 Non-species related breakpoints have been determined mainly on the basis of pharmacokinetic/pharmacodynamic data and are independent of MIC distributions of specific species. They are for use only for species not mentioned above.
The CLSI (Clinical and Laboratory Standards Institute, formerly NCCLS) recommended MIC breakpoints for levofloxacin, separating susceptible from intermediately susceptible organisms and intermediately susceptible from resistant organisms are presented in the below table for MIC testing (μg/mL) or disc diffusion testing (zone diameter [mm] using a 5 μg levofloxacin disc).
CLSI recommended MIC and disc diffusion breakpoints for levofloxacin (M100-S17, 2007):
Pathogen
|
Susceptible
|
Resistant
|
Enterobacteriaceae
|
|
|
Non Enterobacteriaceae
|
|
|
Acinetobacter spp.
|
|
|
Stenotrophomonas maltophilia
|
|
|
Staphylococcus spp.
|
|
|
Enterococcus spp.
|
|
|
H.influenzae
M.catarrhalis 1
|
|
|
Streptococcus pneumoniae
|
|
|
Beta-haemolytic Streptococcus
|
|
|
1 The absence or rare occurrence of resistant strains precludes defining any results categories other than 'susceptible'. For strains yielding results suggestive of a 'non-susceptible' category, organism identification and antimicrobial susceptibility test results should be confirmed by a reference laboratory using CLSI reference dilution method.
Antibacterial spectrum
The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
COMMONLY SUSCEPTIBLE MICROORGANISMS
Aerobic Gram-positive bacteria
Staphylococcus aureus* methicillin-susceptible
Staphylococcus saprophyticus
Streptococci, groups 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
