Nevotic^® is indicated in adults for the treatment of the following infections (see sections 4.4 and 5.1):

·         Acute pyelonephritis and complicated urinary tract infections (see section 4.4).

·         Chronic bacterial prostatitis.

·         Inhalation anthrax: for post-exposure prophylaxis and as curative treatment (see section 4.4).

In the below-mentioned infections Nevotic^® 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 bacterial sinusitis.

·         Acute exacerbation of chronic obstructive pulmonary disease including bronchitis.

·         Community-acquired pneumonia.

·         Complicated skin and soft-tissue infections.

·         Uncomplicated cystitis (see section 4.4).

Nevotic^® can also be used to continue a course of treatment in patients who have shown improvement during initial treatment with intravenous levofloxacin.
Consideration should be given to the official guidance on the appropriate use of antibacterial agents.

Do

Nevotic^® film-coated tablets are administered once or twice daily. The dosage depends on the type and severity of the infection and the susceptibility of the presumed causative pathogen.
Nevotic^® tablets can also be used to continue a course of treatment in patients who have shown improvement during initial treatment with intravenous levofloxacin. Given the bioequivalence of the parenteral and oral forms, the same dose can be used.

Dosage in patients with normal renal function (creatinine clearance >50 ml/min)

Posology
For Nevotic^®, the following dosage recommendations can be given:
See table above
Special patient groups
See table below
Impaired liver function
No dose adjustment is required, as levofloxacin is not metabolized to any relevant extent in the liver and is mainly excreted by the kidneys.
Elderly patients
Apart from taking renal function into consideration, no further dose adjustment is required in elderly patients (see section 4.4 “Tendinitis and tendon rupture” and “QT interval prolongation”).

Paediatric population
Nevotic^® is contraindicated in children and growing adolescents (see section 4.3).
Method of administration
The film-coated tablets should be swallowed without chewing with sufficient liquid. They may be divided at the score line to adjust the dose. The film-coated tablets may be taken during or between meals. The film-coated tablets should be taken at least 2 hours before or after taking iron salts, zinc salts, magnesium- or aluminium-containing antacids, didanosine (applies only to formulations with aluminium- or magnesium-containing buffering agents) or sucralfate, as a reduction in absorption may otherwise occur (see section 4.5).

The use of levofoxacin 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 levofoxacin should only be initiated in the absence of alternative treatment options and after careful benefit/risk assessment (see also section 4.3).
Risks of resistance
Methicillin-resistant S. aureus are likely to possess co-resistance to fluoroquinolones (including levofloxacin). In known or suspected MRSA infections, levofloxacin is therefore not recommended for treatment, unless laboratory results confirm susceptibility of the pathogen to levofloxacin (and commonly recommended antibiotics for the treatment of MRSA are not considered to be indicated). 

1 No additional doses are required after haemodialysis or continuous ambulatory peritoneal dialysis (CAPD).
Levofloxacin can be used for the treatment of acute bacterial sinusitis or acute exacerbation of chronic bronchitis when these infections have been professionally diagnosed.
Resistance of E. coli – the most common pathogen in urinary tract infections – to fluoroquinolones varies within the European Union. When prescribing, physicians should consider the local prevalence of resistance in E. coli to fluoroquinolones.
Inhalation anthrax: Use in humans is based on in vitro Bacillus anthracis susceptibility data and on experimental data in animals together with limited human data. Treating physicians should refer to national or international consensus papers when treating anthrax.
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 older patients, patients with renal impairment, patients with solid organ transplants, in patients receiving daily doses of 1000 mg levofloxacin 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 with levofloxacin 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 (including several weeks after the end of treatment), may be indicative of Clostridium difficile-associated disease (CDAD). CDAD may range in severity from mild to its most severe (life-threatening) form, i.e. pseudomembranous colitis (see section 4.8). It is therefore important to consider this diagnosis if serious diarrhoea develops in patients during or after treatment with levofloxacin. If CDAD is suspected or confirmed, treatment with levofloxacin must be halted immediately and appropriate treatment initiated. Antiperistaltic agents are contraindicated in such cases.
Patients predisposed to seizures
Quinolones can lower the seizure threshold and may trigger seizures. Levofloxacin is contraindicated in patients with known epilepsy (see section 4.3) and, as with other quinolones, should be used only with extreme caution in patients predisposed to epileptic seizures or receiving concomitant treatment with medicinal products that lower the seizure threshold, such as theophylline (see section 4.5). If convulsive seizures occur (see section 4.8), treatment with levofloxacin should be discontinued.
Patients with glucose-6-phosphate dehydrogenase deficiency
Patients with latent or existing glucose-6-phosphate dehydrogenase deficiency may be prone to haemolytic reactions when treated with quinolones. When treating such patients with levofloxacin, potential occurrence of haemolysis should therefore be closely monitored.
Patients with impaired renal function
Since levofloxacin is excreted mainly by the kidneys, the dose should be adjusted in patients with impaired renal function (see section 4.2).
Hypersensitivity reactions
Levofloxacin can induce serious, potentially life-threatening hypersensitivity reactions (e.g. angioedema and even anaphylactic shock), occasionally even after the first dose (see section 4.8). Patients should discontinue treatment immediately and inform 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, abnormal blood glucose levels (including hyperglycaemia and hypoglycaemia) have been reported, occurring more frequently in the elderly and usually in diabetics receiving concomitant treatment with an oral antidiabetic (e.g. glibenclamide) or with insulin. There are known cases of hypoglycaemic coma. In diabetic patients, careful monitoring of blood glucose levels is recommended (see section 4.8).
Treatment with levofloxacin should be stopped immediately if a patient reports blood glucose disturbance and alternative nonfluoroquinolone antibacterial therapy should be considered.
Prevention of photosensitisation
Photosensitisation has 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 and for up to 48 hours after treatment, in order to avoid photosensitisation.
Patients on treatment with vitamin K antagonists
Due to possible elevation of coagulation values (PT/INR) and/or bleeding in patients treated with levofloxacin in combination with vitamin K antagonists (e.g. warfarin), coagulation values should be monitored when these medicines are used concomitantly (see section 4.5).
Psychotic reactions
Psychotic reactions have been reported in patients on treatment with 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). If any patient develops such reactions, levofloxacin must be discontinued immediately at the first signs or symptoms of these reactions and patients should be advised to contact their prescriber for advice. Alternative nonfluoroquinolone antibacterial therapy should be considered and appropriate measures instituted. Caution is indicated when using levofloxacin in psychotic patients or those with a history of psychiatric illness.
QT interval prolongation
Fluoroquinolones, including levofloxacin, should only be used with caution in patients with known risk factors for prolongation of the QT interval such as, for example:
− Congenital long QT syndrome.
− Concomitant use of medicinal products 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).
− Cardiac disease (e.g. heart failure, myocardial infarction, bradycardia).

Elderly patients and women may be more sensitive to QTc-prolonging medications. Fluoroquinolones, including levofloxacin, should therefore be used with caution in these patients (see sections 4.2 “Elderly patients”, 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 and even fatal hepatic failure have been reported with levofloxacin, especially in patients with severe underlying diseases/comorbidities, e.g. sepsis (see section 4.8). Patients should be advised to stop treatment and consult their doctor if signs and symptoms of hepatic disease develop, such as anorexia, jaundice, dark urine, pruritus and tender abdomen.
Exacerbation of myasthenia gravis
Fluoroquinolones, including levofloxacin, may trigger neuromuscular blockade and exacerbate muscle weakness in patients with myasthenia gravis. Severe postmarketing adverse reactions (including death or the requirement for respiratory support) are associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin is therefore not recommended for patients with known myasthenia gravis.
Visual disturbances
If vision becomes impaired or other effects on the eyes are experienced, an eye specialist should be consulted immediately (see sections 4.7 and 4.8).
Superinfection
In prolonged treatment with levofloxacin, overgrowth of non-susceptible organisms may occur. In the event of superinfection, appropriate measures should be undertaken.
Interference with laboratory results
In patients treated with levofloxacin, opiate detection in urine may give false-positive results. Positive results may have to be confirmed by more specific methods.
Levofloxacin may inhibit the growth of Mycobacterium tuberculosis and hence lead to false-negative results in the bacteriological diagnosis of tuberculosis.
Aortic Aneurysm and Dissection
Epidemiologic studies report an increased risk of aortic aneurysm and dissection after intake of fluoroquinolones, particularly in the older population.
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 in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or in presence of other risk factors or conditions predisposing for aortic aneurysm and dissection (e.g. Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet’s disease, hypertension, known atherosclerosis).
In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.

Effects of other medicinal products on Nevotic^®
Iron salts, zinc salts, magnesium- or aluminium-containing antacids, didanosine
Levofloxacin absorption is significantly reduced when iron salts, magnesium- or aluminium-containing antacids or didanosine (applies only to didanosine formulations with aluminium- or magnesium-containing buffering agents) are administered concomitantly with Nevotic^® tablets. Concurrent use of fluoroquinolones with multi-vitamin preparations containing zinc appears to reduce absorption. It is recommended that preparations containing divalent or trivalent cations, such as iron- or zinc salts, or magnesium- or aluminium-containing antacids or didanosine (applies only to didanosine formulations with aluminium- or magnesium-containing buffering agents) should not be taken 2 hours before and for up to 2 hours after the administration of Nevotic^® film-coated tablets (see section 4.2). Calcium salts have been shown to have a minimal effect on the absorption of levofloxacin after oral administration.
Sucralfate
The bioavailability of levofloxacin film-coated tablets is significantly reduced when co-administered with sucralfate. If the patient must be treated concurrently with sucralfate and Nevotic^® film-coated tablets, it is best to administer sucralfate 2 hours after Nevotic^® film-coated tablets (see section 4.2).
Theophylline, fenbufen or similar non-steroidal anti-inflammatory drugs
No pharmacokinetic interactions of levofloxacin were demonstrated with theophylline in a clinical study. However, a pronounced lowering of the seizure threshold may occur when quinolones are given concurrently with theophylline, non-steroidal anti-inflammatory drugs or other agents that lower the cerebral seizure threshold.
Levofloxacin concentrations were about 13% higher during co-medication with 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%), as both medicines are capable of blocking the renal tubular secretion of levofloxacin. However, at the doses tested in the study, the statistically significant kinetic differences are unlikely to be of clinical relevance.
Levofloxacin should be used with caution when co-administering medicinal products that affect tubular renal secretion, e.g. probenecid and cimetidine. This particularly applies to patients with renal insufficiency.
Other information
In clinical pharmacology studies, no clinically relevant effect on the pharmacokinetics of levofloxacin was shown when the following medicinal products were co-administered: calcium carbonate, digoxin, glibenclamide, ranitidine.
Effect of Nevotic^® on other medicinal products
Ciclosporin
The half-life of ciclosporin was prolonged by 33% upon co-administration of levofloxacin.
Vitamin K antagonists
Prolongation of the prothrombin time (increase in INR/decrease in thromboplastin time) and/or even bleeding have been reported in patients concurrently treated with levofloxacin and vitamin K antagonists (e.g. warfarin). Such bleeding may even be severe. Coagulation values should therefore be monitored in patients treated with vitamin K antagonists (see section 4.4).
Medicinal products known to prolong the QT interval
Levofloxacin, like other fluoroquinolones, should only be used with caution in patients concurrently taking other medicinal products 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 information
A pharmacokinetic study showed that levofloxacin exerts no effect on the pharmacokinetics of theophylline (a test substrate for CYP1A2), indicating that levofloxacin is not a CYP1A2 inhibitor.
Other forms of interaction
Food
There is no clinically relevant interaction with food. Nevotic^® film-coated tablets can therefore be taken irrespective of food intake.

Pregnancy
There are only few data on 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).
Nevertheless, levofloxacin must not be used in pregnant women, as studies in humans are lacking and experimental data in animals indicate the risk of possible damage by fluoroquinolones to the cartilage tissue of weight-bearing joints in growing animals (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 breast milk; however, other fluoroquinolones are known to be excreted in breast milk. Due to the lack of studies in humans and because experimental data in animals indicate a risk of possible damage by fluoroquinolones to the cartilage tissue of weight-bearing joints in growing animals, levofloxacin 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.

Some undesirable effects (e.g. light-headedness/dizziness, drowsiness, visual disturbances) may impair the patient’s ability to concentrate and react, and may therefore constitute a risk in situations where these abilities are of special importance (e.g. driving a car or using machines).

The following information is based on data from clinical studies with more than 8300 patients and on extensive post-marketing experience.
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.

^a Anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose

^b Mucocutaneous reactions may sometimes occur even after the first dose

Other undesirable effects which have been associated with fluoroquinolone administration include:

- attacks of porphyria in patients with porphyria

* 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).

To report any side effect(s):

•Saudi Arabia:

The National Pharmacovigilance Center (NPC):

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

•United Arab of Emirates:

Pharmacovigilance and Medical Device Section

P.O. Box: 1853, Tel: 80033784

Email: pv@ede.gov.ae

Drug Department, Ministry of Health & Prevention

Dubai-UAE.

• Sultanate of Oman

Department of Pharmacovigilance & Drug Information

Drug Safety Center

Ministry of health, Sultanate of Oman

Phone No: 22357687 / 22357690

Fax: 22358489

Email: pharma-vigil@moh.gov.om

Website: www.moh.gov.om

•Other GCC States:

Please contact the relevant competent authority.

According to toxicity studies in animals or clinical pharmacology studies with supratherapeutic doses, the most important symptoms to be expected following acute overdose of Levofloxacin film-coated tablets are central nervous disturbances (confusion, light-headedness, impairment of consciousness and seizures), prolongation of the QT interval and gastrointestinal disturbances such as nausea and mucosal erosions.
CNS effects (including confusion, seizures, hallucinations and tremor) have been observed in post-marketing experience.
In the event of an overdose, symptomatic treatment should be instituted. ECG monitoring should be undertaken due to the possible occurrence of QT interval prolongation. Antacids may be used for protection of the gastric mucosa. Haemodialysis, including peritoneal dialysis and CAPD, are unable to eliminate levofloxacin effectively. No specific antidote exists.

Pharmacotherapeutic group: quinolone antibacterials, fluoroquinolones, ATC code: J01MA12.
Levofloxacin is a synthetic antibiotic of the fluoroquinolone group. It is the S (-) enantiomer of the racemate ofloxacin.
Mechanism of action
As a fluoroquinolone antibiotic, levofloxacin acts on the DNA-DNA gyrase complex and topoisomerase IV.
Pharmacokinetic/pharmacodynamic relationship
The degree of the bactericidal activity of levofloxacin depends on the ratio of the maximum serum concentration (Cmax) or the area under the curve (AUC) and the minimal inhibitory concentration (MIC).
Mechanism of resistance
Resistance to levofloxacin is acquired through stepwise mutations at the target site 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 has been observed.
Due to the mechanism of action, there is generally no cross-resistance between levofloxacin and other antibiotic classes.
Breakpoints for susceptibility testing
The EUCAST recommended breakpoints for levofloxacin, used to differentiate susceptible from intermediately susceptible pathogens and intermediately susceptible from resistant pathogens, are presented in the following table for MIC testing (in mg/l).
Clinical MIC breakpoints for levofloxacin according to EUCAST (version 2.0, 2012-01-01):

1. The breakpoints relate to high-dose therapy.
2. Low-level fluoroquinolone resistance (ciprofloxacin MIC is 0.12 to 0.5 mg/l) may occur, but there is no indication that this resistance is of clinical importance in respiratory tract infections with H. influenzae.
3. Strains with MIC values above the “susceptible” breakpoint are very rare or not yet reported. The identification and susceptibility testing of any such isolate must be repeated. If the result is confirmed, the isolate must be sent to a reference laboratory. Until there is evidence regarding clinical response for these confirmed isolates with MIC values above the “resistant” breakpoint, they are to be reported as resistant.
4. Breakpoints relate to oral or intravenous doses of 1 – 2 x 500 mg.
The prevalence of acquired resistance may vary geographically and with time for individual species. Local information on the resistance situation is therefore desirable, particularly for the adequate treatment of severe infections. Expert therapeutic advice should be sought when the local resistance situation is such that the efficacy of levofloxacin in at least some types of infection is questionable.

a Anaphylactic and anaphylactoid reactions may occur even after the first dose.
b Mucocutaneous reactions may 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).
The following statements reflect the European harmonisation data as of August 2012. The data for the current situation for levofloxacin resistance in Germany can be found as additional information after section 11 at the end of this summary of product characteristics.

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 parainfluenzae
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 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).

Absorption
Orally administered levofloxacin is rapidly and almost completely absorbed, with peak plasma concentrations being achieved within about 1 to 2 hours. The absolute bioavailability is 99 to 100%.
Food intake has only a minor effect on the absorption of levofloxacin.
Steady state is reached within 48 hours at a dosage of 500 mg once or twice daily.
Distribution
Approximately 30 to 40% of levofloxacin is bound to serum proteins.
The mean volume of distribution is approximately 100 l after single and repeated administration of 500 mg levofloxacin and indicates widespread distribution into body tissues.
Penetration into tissue and body fluids
Levofloxacin penetrates into bronchial mucosa, pulmonary surfactant film, alveolar macrophages, lung tissue, skin (blister fluid), prostatic tissue and urine. However, penetration of levofloxacin into cerebrospinal fluid is poor.
Biotransformation
Levofloxacin is metabolised only to a very minor extent. The metabolites desmethyl-levofloxacin and levofloxacin N-oxide represent less than 5% of the dose excreted with the urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.
Elimination
Following oral and intravenous administration of levofloxacin, the substance is eliminated relatively slowly from the plasma (t½: 6 – 8 hours). Excretion is primarily by the renal route (>85% of the administered dose).
The mean apparent clearance of levofloxacin following a single 500 mg dose was 175 ± 29.2 ml/min.
There are no major differences with regard to the pharmacokinetics of levofloxacin after intravenous or oral administration, suggesting that the oral and intravenous routes of administration are interchangeable.
Linearity
Levofloxacin shows linear pharmacokinetics within the dose range of 50 to 1000 mg.
Special patient groups
Patients with impaired renal function
The pharmacokinetics of levofloxacin are affected by renal dysfunction. With decreasing renal function, renal elimination and clearance are reduced and elimination half-lives are increased (see table).
Pharmacokinetics in renal insufficiency following single oral 500 mg dose:

Elderly patients
There are no significant differences with regard to pharmacokinetics between young and elderly patients, apart from those associated with altered creatinine clearance.
Gender differences
A separate analysis for male and female subjects showed small to marginal differences in the pharmacokinetics of levofloxacin. There are no indications that these gender-specific differences are of clinical relevance

Non-clinical data reveal no special hazard for humans (based on conventional studies of single dose toxicity, repeated dose toxicity, carcinogenicity and toxicity to reproduction and development).
Levofloxacin caused no impairment of fertility or reproductive performance in rats and its only effect on foetuses was delayed maturation as a result of maternal toxicity.
Levofloxacin induced no gene mutations in bacterial or mammalian cells but did induce chromosome aberrations in Chinese hamster lung cells in vitro. This can be attributed to inhibition of topoisomerase II. In vivo tests (micronucleus, sister chromatid exchange, UDS, dominant lethal tests) revealed no genotoxicity.
Only at very high doses did levofloxacin show a phototoxic potential in mice. Levofloxacin showed no genotoxic potential in a photomutagenicity assay and it reduced tumour development in a photocarcinogenicity study.
In common with other fluoroquinolones, levofloxacin showed effects on cartilage (blistering and cavities) in rats and dogs. These effects were more marked in young animals.

Microcrystalline cellulose, sodium starch glycolate, povidone K30, colloidal anhydrous silica, magnesium stearate, Opadry OY-L white, black iron oxide, yellow iron oxide, polyethylene glycol 6000.

None

Store below 30°C.

Nevotic^® 500mg: Beige to brownish yellow oval deep biconvex film coated tablet engraved with PhI on one face, packed in PVC /PVDC/Alu blisters, intended for oral use.

Pack size: 7 Film Coated Tablets (7 tablets/blister, 1 blister/pack).

10 Film Coated Tablets (10 tablets/blister, 1 blister/pack).

No special requirements.