Levoact tablets are indicated in adults for the treatment of the following infections (see sections 4.4 and 5.1):
• Acute bacterial sinusitis
• Acute exacerbations of chronic bronchitis
• Community-acquired pneumonia
• Complicated skin and soft tissue infections.
For the above-mentioned infections Levoact should be used only when it is considered inappropriate to use antibacterial agents that are commonly recommended for the initial treatment of these infections.
• Pyelonephritis and complicated urinary tract infections (see section 4.4)
• Chronic bacterial prostatitis,
• Uncomplicated cystitis (see section 4.4)
• Inhalation Anthrax: post exposure prophylaxis and curative treatment (see section 4.4).
Levoact may also be used to complete a course of therapy in patients who have shown improvement during initial treatment with intravenous levofloxacin.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Levoact tablets administered once or twice daily.
The dosage depends on the type and severity of the infection and the susceptibility of the presumed causative pathogen.
Levoact tablets may also be used to complete a course of therapy in patients who have shown improvement during initial treatment with intravenous levofloxacin; given the bioequivalence of
the parenteral and oral forms, the same dosage can be used.
Posology
The following dose recommendations can be given for Levoact:
Dosage in patients with normal renal function (creatinine clearance > 50 ml/min)
Indication
Daily dose regimen (according to severity)
Duration of the treatment (according to severity)
Acute bacterial sinusitis
500 mg once daily
10 – 14 days
Acute bacterial exacerbations of chronic bronchitis
500 mg once daily
7 – 10 days
Community-acquired pneumonia
500 mg once or twice daily
7 – 14 days
Pyelonephritis
500 mg once daily
7 – 10 days
Uncomplicated cystitis
250 mg once daily
3 days
Complicated urinary tract infections
500 mg once daily
7 – 14 days
Chronic bacterial prostatitis
500 mg once daily
28 days
Complicated skin and soft tissue infections
500 mg once or twice daily
7 – 14 days
Inhalation Anthrax
500 mg once daily
8 weeks
Special populations
Impaired renal function (creatinine clearance ≤ 50 ml/min)
Creatinine clearance
Dose regimen
250 mg/24 h
500 mg/24 h
500 mg/12 h
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
1 No additional doses are required after haemodialysis or continuous ambulatory peritoneal dialysis (CAPD)
Impaired liver function
No adjustment of dosage is required since levofloxacin is not metabolized to any relevant extent by the liver and is mainly excreted by the kidneys.
Elderly population
No adjustment of dose is required in the elderly, other than that imposed by consideration of renal function (see section
4.4 “Tendinitis and tendon rupture” and “QT interval prolongation”).
Paediatric population
Levofloxacin is contraindicated in children and growing adolescents (see section 4.3).
Method of administration
Levoact tablets should be swallowed without crushing and with sufficient amount of liquid. They may be divided at the score line to adapt the dose. The tablets may be taken during meals or between meals. Levoact tablets should be taken at least two hours before or after iron salts, zinc salts, magnesium- or aluminium-containing antacids, or didanosine (only didanosine formulations with aluminium or magnesium containing buffering agents), and sucralfate administration, since reduction of absorption can occur (see section 4.5).

Levoact tablets must not be used: • in patients hypersensitive to levofloxacin, or other quinolones or any of the excipients listed in section 6.1, • in patients with epilepsy, • in patients with history of tendon disorders related to fluoroquinolone administration, • in children or growing adolescents, • during pregnancy, • in breast-feeding women

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 (and commonly recommended antibacterial agents for the treatment of MRSA-infections are considered inappropriate).
Levofloxacin may be used in the treatment of Acute Bacterial Sinusitis and Acute Exacerbation of Chronic Bronchitis when these infections have been adequately diagnosed.
Resistance to fluoroquinolones of E. coli – the most common pathogen involved in urinary tract infections – varies across the European Union. Prescribers are advised to take into account the local prevalence of resistance in E. coli to fluoroquinolones.
Inhalation Anthrax: Use in humans is based on in vitro Bacillus anthracis susceptibility data and on animal experimental data together with limited human data. Treating physicians should refer to national and/or international consensus documents regarding the treatment of anthrax.
Tendinitis and tendon rupture
Tendinitis may rarely occur. It most frequently involves the Achilles tendon and may lead to tendon rupture, sometimes bilateral, may occur within 48 hours of starting treatment with levofloxacin and have been reported up to several months after discontinuation of treatment.. The risk of tendinitis and tendon rupture is increased in patients aged over 60 years, in patients receiving daily doses of 1000 mg and in patients using corticosteroids. The daily dose should be adjusted in elderly patients based on creatinine clearance (see section 4.2). 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 (see section 4.3 and 4.8).
Clostridium difficile-associated disease
Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with levofloxacin (including several weeks after treatment), may be symptomatic of Clostridium difficile-associated disease (CDAD). CDAD may range in severity from mild to life threatening, the most severe form of which is pseudomembranous colitis (see section 4.8). It is therefore important to consider this diagnosis in patients who develop serious diarrhoea during or after treatment with levofloxacin. If CDAD is suspected or confirmed, levofloxacin should be stopped immediately and appropriate treatment initiated without delay. Anti-peristaltic medicinal products are contraindicated in this clinical situation.
Patients predisposed to seizures
Quinolones may lower the seizure threshold and may trigger seizures. Levofloxacin is contraindicated in patients with a history of epilepsy (see section 4.3) and, as with other quinolones, should be used with extreme caution in patients predisposed to seizures or concomitant treatment with active substances that lower the cerebral seizure threshold, such as theophylline (see section 4.5). In case
of convulsive seizures (see section 4.8), treatment with levofloxacin should be discontinued.
Patients with 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. Therefore, if levofloxacin has to be used in these patients, potential occurrence of haemolysis should be monitored.
Patients with renal impairment
Since levofloxacin is excreted mainly by the kidneys, the dose of levofloxacin should be adjusted in patients with renal impairment (see section 4.2).
Hypersensitivity reactions
Levofloxacin can cause serious, potentially fatal hypersensitivity reactions (e.g. angioedema up to anaphylactic shock), occasionally following the initial dose (see section 4.8). Patients should discontinue treatment immediately and contact their physician or an emergency physician, who will initiate appropriate emergency measures.
Severe bullous reactions
Cases of severe bullous skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported with levofloxacin (see section 4.8). Patients should be advised to contact their doctor immediately prior to continuing treatment if skin and/or mucosal reactions occur.
Dysglycaemia
As with all quinolones, disturbances in blood glucose, including both hyperglycaemia and hypoglycaemia have been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycaemic agent (e.g. glibenclamide) or with insulin. Cases of hypoglycaemic coma have been reported. In diabetic patients, careful monitoring of blood glucose is recommended (see section 4.8).
Prevention of photosensitisation
Photosensitisation has been reported with levofloxacin (see section 4.8). It is recommended that patients should not expose themselves unnecessarily to strong sunlight or artificial UV rays (e.g. sunray lamp or solarium), during treatment and for 48 hours following treatment discontinuation in order to prevent photosensitisation.
Patients treated with vitamin K antagonists
Due to possible increase in coagulation tests (PT/INR) and/or bleeding in patients treated with levofloxacin in combination with a vitamin K antagonist (e.g. warfarin), coagulation tests should be monitored when these drugs are given concomitantly (see section 4.5).
Psychotic reactions
Psychotic reactions have been reported in patients receiving quinolones, including levofloxacin. In very rare cases these have progressed to suicidal thoughts and 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.
QT interval prolongation
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)
- cardiac disease (e.g. heart failure, myocardial infarction, bradycardia)
Elderly patients and women may be more sensitive to QTc-prolonging medications. Therefore, caution should be taken when using fluoroquinolones, including levofloxacin, in these populations (see sections 4.2 Elderly, 4.5, 4.8 and 4.9).
Peripheral neuropathy
Peripheral sensory neuropathy and peripheral sensory motor neuropathy have been reported in patients receiving fluroquinolones, including levofloxacin, which can be rapid in its onset (see section 4.8). Levofloxacin should be discontinued if the patient experiences symptoms of neuropathy in order to prevent the development of an irreversible condition.
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.
Exacerbation of myasthenia gravis
Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Post marketing serious adverse reactions, including deaths and the requirement for respiratory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin is not recommended in patients with a known history of myasthenia gravis.
Vision disorders
If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately (see sections 4.7 and 4.8).
Superinfection
The use of levofloxacin, especially if prolonged, may result in overgrowth of non-susceptible organisms. If superinfection occurs during therapy, appropriate measures should be taken.
Interference with laboratory test
In patients treated with levofloxacin, determination of opiates in urine may give false-positive results. It may be necessary to confirm positive opiate screens by more specific method.
Levofloxacin may inhibit the growth of Mycobacterium tuberculosis and, therefore, may give false-negative results in the bacteriological diagnosis of tuberculosis

Effect of other medicinal products on levofloxacin
Iron salts, zinc salts, magnesium- or aluminium-containing antacid, didanosines
Levofloxacin absorption is significantly reduced when iron salts, or magnesium- or aluminium- containing antacids, or didanosine (only didanosine formulations with aluminium or magnesium containing buffering agents) are administered concomitantly with Levoact tablets. Concurrent administration of fluoroquinolones with multi-vitamins containing zinc appears to reduce their oral absorption. It is recommended that preparations containing divalent or trivalent cations such as iron salts, zinc salts or magnesium- or aluminium-containing antacids, didanosine (only didanosine formulations with aluminium or magnesium containing buffering agents) should not be taken 2 hours before or after Levoact tablet administration (see section 4.2). Calcium salts have a minimal effect on the oral absorption of levofloxacin.
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 aeffect 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 I I antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see section 4.4 QT interval prolongation).
Other relevant information
In a pharmacokinetic interaction study, levofloxacin did not affect the pharmacokinetics of theophylline (which is a probe substrate for CYP1A2), indicating that levofloxacin is not a CYP1A2 inhibitor.
Other forms of interactions
Food
There is no clinically relevant interaction with food. Levoact tablets may therefore be administered
regardless of food intake.

Pregnancy
There are limited amount of data from the use of levofloxacin in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). However, in the absence of human data and due to that experimental data suggest a risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, levofloxacin must not be used in pregnant women (see section 4.2 and 5.3).
Breast-feeding
The product is contraindicated in breast-feeding women. There is insufficient information on the excretion of levofloxacin in human milk; however other fluoroquinolones are excreted in breast milk. In the absence of human data and due to the experimental data suggests 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).
Fertility
Levofloxacin caused no impairment of fertility or reproductive performance in rats.

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).

The information given below is based on data from clinical studies in more than 8,300 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.
System organ class
Common (≥1/100 to
<1/10)
Uncommon (≥1/1,000 to <1/100)
Rare (≥1/10,000 to < 1/1,000)
Not known (cannot be estimated from
Infections and infestations
Fungal infection including Candidia infection
Pathogen resistance
Blood and lymphatic system disorders
Leukopenia Eosinophilia
Thrombocytopenia Neutropenia
Pancytopenia Agranulocytosis Haemolytic anaemia
Immune system disorders
Angioedma
Hypersensitivity (see section 4.4)
Anaphylactic shocka
Anaphylactoid shocka (see section 4.4)
Metabolism and nutrition disorders
Anorexia
Hypoglycaemia particularly in diabetic patients (see section 4.4)
Hyperglycaemia
Hypoglycaemic coma (see section 4.4)
Psychiatric disorders
Insomnia
Anxiety Confusional state Nervousness
Psychotic reaction (with e.g. hallucinations, paranoia)
Depression Agitation Abnormal dreams Nightmares
Psychotic disorders with self-endangering behaviour including suicidal ideation or suicide attempt (see section 4.4)
Nervous system disorders
Headache Dizziness
Somnolence Tremor Dysgeusia
Convulsions (see section 4.3 and 4.4)
Parasethesia
Peripheral sensory neuropathy (see section 4.4)
Peripheral sensory motor neuropathy (see section 4.4)
Parosmia including anosmia
Dyskinesia
Extrapyramidal disorder
Ageusia Synocope
Benign intracranial hypertension
Eye disorders
Visual disturbances such as blurred vision (see section 4.4)
Transient vision loss (see section 4.4)
Ear and Labyrinth disorders
Vertigo
Tinnitus
Hearing loss Hearing impaired
Cardiac disorders
Tachycardia Palpitation
Ventricular tachycardia, which may result in cardiac arrest
Venticular arrhythmia and torsade de pointes (reported predominantly in patients with risk factors of QT prolongation), electrocardiogram QT prolonged (see sections 4.4 and 4.9)
Vascular disorders
Applies to i.v. form
Hypotension
only: Phlebitis
Respiratory, thoracic and medistinal disorders
Dyspnoea
Bronchospasm Pneumonitis
Gastro-intestinal disorders
Diarrhoea Vomiting Nausea
Abdominal pain Dyspepsia Flatulence Constipation
Diarrhoea – haemorrhagic which in very rare cases may be indicative of enterocolitis, including pseudomembranous colitis (see section 4.4)
Pancreatitis
Hepatobiliary disorders
Hepatic enzyme increased (ALT/AST, alkaline phosphatase, CGT)
Blood bilirubin increased
Jaundice and severe liver injury, including cases with fatal acute liver failure, primarily with severe underlying diseases (see section 4.4)
Skin and subcutaneous tissue disordersb
Rash Pruritus Urticaria
Hyperhidrosis
Toxic epidermal necrolysis
Stevens-Johnson syndrome
Erythema multiforme
Photosensitivity reaction (see section 4.4)
Leukocytoclastic vasculitis
Musculoskeletal and connective tissue disorders
Arthralgia Myalgia
Tendon disorders (see sections 4.3 and 4.4) including tendinitis (e.g. Achilles tendon)
Muscle weakness which may be of special importance in patients with myasthenia gravis (see section 4.4)
Rhabdomyolysis
Tendon rupture (e.g. Achilles tendon) (see sections 4.3 and 4.4)
Ligament rupture Muscle rupture Arthritis
Renal and Urinary disorders
Blood creatinine increased
Renal failure acute (e.g. due to interstitial
General disorders and administration site conditions
Applies to i.v. form only:
Infusion site reaction (pain, reddening)
Asthenia
Pyrexia
Pain (including pain in back, chest, and extremities)
aAnaphylactic and anaphylactoid reactions may sometimes occur even after the first dose
bMucocutaneous reactions may sometimes occur even after the first dose
Other undesirable effects which have been associated with fluoroquinolones administration include:
• attacks of porphyria in patients with porphyria.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
To report any side effect(s):
The National Pharmacovigilance and Drug Safety Centre (NPC)
• Fax: +966-11-205-7662
• Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
• Toll free phone: 8002490000
• E-mail: npc.drug@sfda.gov.sa
• Website: www.sfda.gov.sa/npc

According to toxicity studies in animals or clinical pharmacology studies performed with supra-therapeutic doses, the most important signs to be expected following acute overdose of levofloxacin tablets 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.
CNS effects include confusional state, convulsion, hallucination, and tremor have been observed in post marketing experience.
In the event of overdose, symptomatic treatment should be implemented. ECG monitoring should be undertaken, because of the possibility of QT interval prolongation. 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.

Pharmacotherapeutic group: 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
Resistance to levofloxacin is acquired through a stepwise process by target site mutations in both type I topoisomerases, DNA gyrase and topoisomerase IV. Other resistance mechanisms such as permeation barriers (common Pseudomonas aeruginosa) and efflux mechanisms may affect susceptibility to levofloxacin.
Cross-resistance between levofloxacin and other fluoroquinolones is observed. Due to the mechanism of action, there is generally no cross-resistance between levofloxacin and other classes of antibacterial agents.
Breakpoints
The EUCAST recommended MIC breakpoints for levofloxacin, separating susceptible from intermediately susceptible organisms and intermediately susceptible from resistant organisms are presented in the below table for MIC testing (mg/L).
EUCAST clinical MIC breakpoints for levofloxacin (version 2.0, 2012-01-01)
Pathogen
Susceptible
Resistant
Entecobacteriaceae
≤ 1 mg/L
>2 mg/L
Pseudomonas spp.
≤ 1 mg/L
>2 mg/L
Acinetobacter spp.
≤ 1 mg/L
>2 mg/L
Staphylococcus spp.
≤ 1 mg/L
>2 mg/L
S. pneumoniae1
≤ 2mg/L
> 2 mg/L
Streptococcus A, B, C ,G
≤ 1 mg/L
>2 mg/L
H. influenzae2,3
<1 mg/L
>1 mg/L
M. catarrhalis3
<1 mg/L
>1 mg/L
Non-species related breakponts4
≤ 1 mg/L
>2 mg/L
1The breakpoints for levofloxacin relate to high dose therapy.
2Low-level fluoroquinolone resistance (ciprofloxacin MICs of 0.12 -05 mg/l) may occur but there is no evidence that this resistance is of clinical importance in respiratory tract infections with H. influenza.
3Strains with MIC values above the susceptible 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. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint they should be reported resistant.
4Breakpoints apply to an oral dose of 500 mg x 1 to 500 mg x 2 and an intravenous dose of 500 mg x 1 to 500 mg x 2..
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 Bacillus anthracis
Staphylococcus aureus* methicillin susceptible Staphylococcus saprophyticus
Stretococci, groups C and G Streptococcus agalactiae Streptococcus pneumoniae* Streptococcus pyogenes*
Aerobic Gram-negative bacteria Eikenella corrodens
Haemophilus influenzea Haemophilus para-influenzae Klebsiella oxytoca
Moraxella catarrhalis Pasteurella multocida Proteus vulgaris Providencia rettgeri Anaerobic bacteria Peptostreptococcus Other
Chlamydophila pneumoniae Chlamydophila psittaci Chlamydia trachomatis Legionella pneumophila Mycoplasma pneumoniae Mycoplasma hominis Ureaplasma urealyticum
SPECIES FOR WHICH ACQUIRED RESISTANCE MAY BE A PROBLEM
Aerobic Gram-positive bacteria
Enterococcus faecalis
Staphylococcus aureus methicillin-resistant# Coagulase negative Staphylococcus spp
Aerobic Gram-negative bacteria Acinetobacter baumanni
Citrobacter freundi Enterobacter aerogenes Enterobacter cloacae Escherichia coli
Klebsiella pheumoniae Morganella morganii Proteus mirablis 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.

Orally administered levofloxacin is rapidly and almost completely absorbed with peak plasma concentrations being obtained within 1 – 2 h. The absolute bioavailability is 99 - 100%.
Food has little effect on the absorption of levofloxacin.
Steady state conditions are reached within 48 hours following a 500 mg once or twice daily dosage regimen.
Distribution
Approximately 30 – 40% of levofloxacin is bound to serum protein. The mean volume of distribution of levofloxacin is approximately 100 l after single and repeated doses, indicating widespread distribution into body tissues.
Penetration into tissues and body fluids:
Levofloxacin has been shown to penetrate into bronchial mucosa, epithelial lining fluid alveolar macrophages, lung tissue, skin (blister fluid), prostatic tissue and urine. However, levofloxacin has poor penetration intro cerebro-spinal fluid.
Biotransformation
Levofloxacin is metabolised to a very small extent, the metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for < 5% of the dose excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.
Elimination
Following oral and intravenous administration of levofloxacin, it is eliminated relatively slowly from the plasma (t½: 6 – 8 h). Excretion is primarily by the renal route (>85% of the administered dose).
The mean apparent total body clearance of levofloxacin following a 500 mg single dose was 175 +/- 29.2 ml/min.
There are no major differences in the pharmacokinetics of levofloxacin following intravenous and oral administration, suggesting that the oral and intravenous routes are interchangeable.
Linearity
Levofloxacin obeys linear pharmacokinetics over a range of 50 to 1000 mg.
Special populations
Subjects with renal insufficiency
The pharmacokinetics of levofloxacin are affected by renal impairment. With decreasing renal function renal elimination and clearance are decreased, and elimination half-lives increased as shown in the table below:
Pharmacokinetics in renal insufficiency following single oral 500 mg dose
Clcr [ml/min]
<20
20 – 49
50 – 80
ClR [ml/min]
13
26
57
t½ [h]
35
27
9
Elderly subjects
There are no significant differences in levofloxacin kinetics between young and elderly subjects, except those associated with differences in creatinine clearance.
Gender differences
Separate analysis for male and female subjects showed a small to marginal gender differences in levofloxacin pharmacokinetics. There is no evidence that these gender differences are of clinical relevance.

Non-clinical data reveal no special hazard based on conventional studies of single dose toxicity, repeated dose toxicity, carcinogenic potential and toxicity to reproduction and development.
Levofloxacin caused no impairment of fertility or reproductive performance in rats and its only effect on foetuses was delayed maturation as a result of maternal toxicity.
Levofloxacin did not induce gene mutations in bacterial or mammalian cells but did induce chromosome aberrations in Chinese hamster cells in vitro. These effects can be attributed to inhibition of topoisomerase II. In vivo tests (micronucleus, sister chromatid exchange, unscheduled DNA synthesis, dominant lethal tests) did not show any genotoxic potential.
Studies in the mouse showed levofloxacin to have phototoxic activity only at very high doses. Levofloxacin did not show any genotoxic potential in a photomutagenicity assay, and it reduced tumour development in a photocarcinogenicity study.
In common with other fluoroquinolones, levofloxacin showed effects on cartilage (blistering and cavities) in rats and dogs. These findings were more marked in young animals.

Tablet core:
Hydroxypropylmethylcellulose
Crospovidone
Microcrystalline cellulose
Colloidal anhydrous silica
Pregelatinized corn starch
Sodium stearyl fumarate
Film coating
Opadry Y-1-7000
Red iron oxide (E -172).

Not applicable

3 years.

Do not store at a temperature above 30ºC

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

White PVC-PVDC-aluminium blisters with film-coated tablets.
The 500 mg tablets are available in 10-tablet packs.

No special requirements