1. Name Of The Medicinal Product
Evoxil 5 mg/ml solution for infusion
2. Qualitative And Quantitative Composition
Each ml of solution for infusion contains 5 mg of levofloxacin (as hemihydrate).
Each 50 ml vial of solution for infusion contains 250 mg of levofloxacin (as hemihydrate).
Each 100 ml vial of solution for infusion contains 500 mg of levofloxacin (as hemihydrate).
Excipients:
Each ml of solution for infusion contains 0.15 mmol (3.54 mg) sodium (as chloride)
50 ml of solution for infusion contains 7.70 mmol (177.10 mg) sodium (as chloride)
100 ml of solution for infusion contains 15.40 mmol (354.20 mg) sodium (as chloride)
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Solution for infusion.
A clear greenish-yellow solution, free from foreign particles.
pH: 4.5 – 5.1
Osmolarity: 290 mOsmol/Kg ± 5%
4. Clinical Particulars
4.1 Therapeutic Indications
In adults for whom intravenous therapy is considered to be appropriate, Evoxil solution for infusion is indicated for the treatment of the following infections when due to levofloxacin-susceptible microorganisms:
• Community-acquired pneumonia (when it is 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).
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology And Method Of Administration
Evoxil 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 (Evoxil 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.
Treatment time
The duration of therapy varies according to the course of the disease (see table below). As with antibiotic therapy in general, administration of Evoxil solution for infusion 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
Evoxil 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 Evoxil 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:
Dosage in patients with normal renal function (creatinine clearance> 50 ml/min)
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1Consideration should be given to increasing the dose in cases of severe infection
Special populations
Impaired renal function (creatinine clearance < 50 ml/min)
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1 No additional doses are required after haemodialysis or continuous ambulatory peritoneal dialysis (CAPD)
Impaired hepatic 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).
Levofloxacin is contraindicated in children and growing adolescents (less than 18 years of age) (see section 4.3)
4.3 Contraindications
Evoxil solution for infusion must not be used:
• in patients hypersensitive to levofloxacin, or other quinolones or any of the excipients,
• in patients with epilepsy,
• in patients with history of tendon disorders related to fluoroquinolone administration,
• in children or growing adolescents (up to age of 18),
• during pregnancy,
• in breast-feeding women.
4.4 Special Warnings And Precautions For Use
In the most severe cases of pneumococcal pneumonia Evoxil 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 500 mg Evoxil 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, (/-isomer of ofloxacin) the infusion should be halted immediately.
Methicillin-resistant Staphylococcus aureus (MRSA)
Methicillin-resistant S. aureus are very likely to possess co-resistance to fluroquinolones, 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 Evoxil tablets may be symptomatic of Clostridium difficile-associated disease, the most severe form of which is pseudomembranous colitis. If pseudomembranous colitis is suspected, levofloxacin for infusion must be stopped immediately and patients should be treated with supportive measures and specific therapy without delay (e.g. oral metronidazole or 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 damage; concomitant treatment with fenbufen and similar non-steroidal anti-inflammatory drugs or with drugs which lower the cerebral seizure threshold, such as theophylline (see 4.5). In case of convulsive seizures, treatment with levofloxacin should be discontinued.
Patients with glucose-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.
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.
Hypoglycaemia
As with all quinolones, hypoglycaemic has been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycaemic 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 artificial UV rays (e.g. sunray lamp or 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 concomitantly (see section 4.5).
Psychotic reactions
Psychotic reactions have been reported in patients receiving quinolones, including levofloxacin. In very rare case 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 a history of psychiatric disease.
Cardiac disorders
Caution should be taken when using fluroquinolones, including levofloxacin, in patients with known risk factors for prolongation of the QT interval such as, for example:
- congenital long QT syndrome
- concomitant use of drugs that are known to prolong the QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, 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 fluroquinolones, 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 methods.
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 contains7.70 mmol (177.10 mg) sodium per 50 ml 15.40 mmol (354.20 mg) sodium per 100 ml of 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
Interaction studies have only been performed in adults.
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 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 renal 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 antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see section 4.4).
4.6 Pregnancy And Lactation
Pregnancy
Reproductive studies in animals did not raise specific concern. However in the absence of human data and due to the experimental risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, levofloxacin must not be used in pregnant women (see section 4.3 and 5.3)
Lactation
In the absence of human data and due to the experimental risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, 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
Certain 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 5,000 patients and on extensive post marketing experience.
The adverse reactions are described according to the MedDRA system organ class below.
Frequencies are defined using the following convention:
Very common (>1/10)
Common ((>1/100, <1/10)
Uncommon ((>1/1,000, <1/100)
Rare (>1/10,000, <1/1,000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
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Other undesirable effects which have been associated with fluoroquinolones 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 Evoxil solution for infusion are central nervous symptoms such as confusion, dizziness, impairment of consciousness, and convulsive seizures, increases in QT interval as well as gastro-intestinal reactions such as nausea and mucosal erosions. In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. Antacids may be used for protection of gastric mucosa. Haemodialysis, including peritoneal dialysis and CAPD, are not effective in removing levofloxacin from the body.
No specific antidote exists.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
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Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class and is the S(-) enatiomer 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)
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1The 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.
2Strains 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.
3Non-species related breakpoints have been determined mainly on the basis of pharmacokinetic/pharmacodynamic data and are independent of MIC distribution of specific species. They are for use only for species not mentioned in the table.
The CLIS (Clinical and Laboratory Standards Institute, formerly NCCLS) recommended MIC breakpoints for levofloxacin, separating susceptible from intermediate 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 5 µg levofloxacin disc).
CLSI recommended MIC and disc diffusion breakpoint for levofloxacin (M100-S17, 3007):
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1The absence of 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
Stretococci, groups C and G
Streptococcus agalactiae
Streptococcus pneumoniae*
Streptococcus pyogenes*
Aerobic Gram-negative bacteria
Burkholderia cepacia$
Eikebella corrodens
Haemophilus influenza*
Haemophilus para-influenza*
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