1. Name Of The Medicinal Product
Evoxil 250 mg film-coated tablets
2. Qualitative And Quantitative Composition
Each film-coated tablet contains levofloxacin hemihydrates equivalent to 250 mg of levofloxacin.
Excipients:
Each tablet contains the excipient FD&C yellow #6/Sunset Yellow aluminium lake.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet.
Pink, oblong, biconvex film-coated tablet with a scoreline.
The tablet can be divided into equal halves.
4. Clinical Particulars
4.1 Therapeutic Indications
In adults with infections of mild to moderate severity, Evoxil tablets are indicated for the treatment of the following infections when due to levofloxacin-susceptible microorganisms:
• Acute bacterial sinusitis (adequately diagnosed according to national and/or local guidelines on the treatment of respiratory tract infections, and when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of this infection or when these have failed to resolve the infection),
• Acute bacterial exacerbations of chronic bronchitis (adequately diagnosed according to national and/or local guidelines on the treatment of respiratory tract infections, and when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of this infection or when these have failed to resolve the infection),
• Community-acquired pneumonia (when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of this infection),
• Uncomplicated urinary tract infections,
• Complicated urinary tract infections (including pyelonephritis),
• Chronic bacterial prostatitis,
• Skin and soft tissue infections.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
4.2 Posology And Method Of Administration
Evoxil tablets administered once or twice daily.
The dosage depends on the type and severity of the infection and the sensitivity of the presumed causative pathogen.
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 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
Evoxil tablets should be swallowed without crushing and with sufficient amount of liquid. They may be divided at the score line to adapt the dosage. The tablets may be taken during meals or between meals. Evoxil tablets should be taken at least two hours before iron salts, antacids and sucralfate administration since reduction of absorption can occur (see section 4.5).
Posology
Dosage in patients with normal renal function (creatinine clearance > 50 ml/min)
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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).
In children
Levofloxacin is contraindicated in children and growing adolescents (less than 18 years of age) (see section 4.3).
4.3 Contraindications
Evoxil tablets 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 levofloxacin may not be the optimal therapy. Nosocomial infections due to P. aeruginosa may require combination therapy.
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).
In infections suspicious for MRSA levofloxacin should be combined with an agent approved to treat MRSA infections.
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, Evoxil tablets 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 Evoxil 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, 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 contains the colouring agent sunset yellow (E110), which may cause allergic reactions.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Effect of other medicinal products on levofloxacin
Iron salts, magnesium- or aluminium-containing antacids
Levofloxacin absorption is significantly reduced when iron salts, buffered formulations or magnesium- or aluminium-containing antacids are administered concomitantly. It is recommended that preparations containing divalent or trivalent cations such as iron salts, buffered formulations or magnesium- or aluminium-containing antacids should not be taken 2 hours before or after Evoxil tablet administration. No interaction was found with calcium carbonate.
Sucralfate
The bioavailability of Evoxil tablets 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 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 QT interval prolongation).
Other forms of interactions
Meals
there is no clinically relevant interaction with food. Evoxil tablets may therefore be administered regardless of food intake.
4.6 Pregnancy And Lactation
Pregnancy
The product is contraindicated during 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
The product is contraindicated in breast-feeding women. 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 levofloxacin 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
Pharmacotherapeutic group: | Antiinfectives 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(-) 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 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).
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*
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
Ureaplasma urealyticum
SPECIES FOR WHICH ACQUIRED RESISTANCE MAY BE A PROBLEM
Aerobic Gram-positive bacteria
Enerococcus faecalis*
Staphylococcus aureus methicillin-resistant
Staphylococcus haemolyticus methicillin-resistant
Aerobic Gram-negative bacteria
Acinetobacter baumannii*
Citrobacter freundii*
Enterobacter aerogenes
Enterbacter agglomerans
Enterobacter cloacae
Escherichia coli*
Morganella morganii
Proteus mirablis*
Providencia stuartii
Pseudomonas aeruginosa*
Serratia marcescens*
Anaerobic bacteria
Bacteroides fragilis
Bacteroides ovatus$
Bacteroides thetaiotamicton$
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 t
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