LEVOBAX

APPROVED

by Order of the Ministry of Health

of Ukraine

as of ____________ No. ______

Registration Certificate

No. _______________________

INSTRUCTION

For medical application of drug

LEVOBAX

 

Formulation:

active substance: levofloxacin;

1 tablet contains: levofloxacin 500 mg;

adjuvants: lactose monohydrate, microcrystalline cellulose, dibasic calcium phosphate, gelatinized starch, povidone, magnesium stearate, talc, crosscarmellose sodium, hypromellose, titanium dioxide (E 171), polyethylene glycol 6000.

Dosage Form. Tablets coated with membrane.

Pharmacotherapeutic Group. Antibacterial drugs of quinolone group. Fluoroquinolones.

ATC Code J0M A12.

Clinical Characteristics.

Indications.

In adults with light and moderate-severity infections Levobax tablets are prescribed for treatment of the following infections caused by levofloxacin-sensitive microorganisms: acute sinusitis, exacerbation of chronic bronchitis, pneumonia, complicated and uncomplicated infections of urinary tracts (including pyelonephritis), skin infections and infections of soft tissues, chronic bacterial prostatitis.

Contraindications.

Hypersensitivity to levofloxacin or other quinolones, epilepsy, patients complaining of side effects on tendons after previous application of quinolones, children’s age, pregnancy, and breast-feeding period.

Method of Application and Dosage.

Levobax tablets are taken once or twice a day. The dose depends on type and severity of infection. Duration of treatment depends on the course of disease and is usually not more than 14 days. It is recommended to continue treatment with Levobax for at least another 48-72 hours after temperature normalization or causative agents destruction confirmed by microbiological tests.

Levobax tablets should be swallowed, not chewed, taken with sufficient amount of liquid. For the purpose of dosage convenience the tablet may be divided with the help of dividing line, tablets may be taken either with meals or at any other time.

Dosage for adult patients with normal renal function in which creatinine clearance is over 50ml/min:

Indications

Daily dose

Number of takings per day

Duration of treatment

Acute sinusitis

500 mg

1

10-14 days

Exacerbation of chronic bronchitis

250-500 mg

1

7-10 days

Non-hospital pneumonia

500 mg

1-2

7-14 days

Uncomplicated infections of urinary tracts

250 mg

1

3 days

Chronic bacterial prostatitis

500 mg

1

28 days

Complicated infections of urinary tracts

250 mg

1

7-10 days

Infections of skin and soft tissues

250-500 mg

1-2

7-14 days

 

Dosage for patients with impaired renal function, in which creatinine clearance is under 50 ml/min:

Creatinine clearance

Dosing procedure (depending on severity of disease)

50-20 ml/min

first dose: 250 mg;

following doses: 125 mg/24 hours

first dose: 500 mg;

following doses: 250 mg/24 hours

first dose: 500 mg;

following doses: 250 mg/12 hours

19-20 ml/min

first dose: 250 mg;

following doses:

125 mg/48 hours

first dose: 500 mg;

following doses: 125 mg/24 hours

first dose: 500 mg;

following doses: 125 mg/12 hours

<10 ml/min, (and in cases of haemodialysis and CAPD1)

first dose:250 mg;

following doses: 125 mg/48 hours.

first dose: 500 mg;

following doses: 125 mg/24 hours

first dose: 500 mg;

following doses: 125 mg/24 hours

 

1 – After haemodialysis or chronic ambulatory peritoneal dialysis (CAPD) additional doses are not required.

If 125 mg dose is required, it is necessary to apply other levofloxacin drug with possibility of such dosing.

Dosing for patients with impaired liver function. Adjustment of dose is not required since levofloxacin is barely metabolized in liver.

Dosing for elderly patients. If the liver function is not compromised, there is no need in dose adjustment.

Side Effects.

Occurrence is determined on the basis of the following reference designation: very often (≥ 1/10), often (≥ 1/100, ≤ 1/10), not often (≥ 1/1000, ≤ 1/100), rarely (≥ 1/10000, ≤1/1000), very rarely (≤ 1/1000), unknown (cannot be evaluated on the basis of available data).

Infections and invasions

Not often: mycosis (and activation of growth of other resistant microorganisms).

On blood system and lymphatic system

Not often: leukopenia, eosinophilia.

Rarely: thrombocytopenia, neutropenia.

Very rarely: agranulocytosis.

Unknown: pancytopenia, haemolytic anaemia.

On immune system

Very rarely: anaphylactic shock (See Section “Peculiarities of Application”).

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

Unknown: hypersensitivity (See Section “Peculiarities of Application”).

Metabolic and eating disorders

Not often: anorexia.

Very rarely: hypoglycaemia, especially in patients with diabetes (See Section “Peculiarities of Application”).

On psychics

Not often: insomnia, nervousness.

Rarely: psychotic disorders, depression, mental confusion, anxiety, agitation, excitement.

Very rarely: psychotic reactions with self-destructive behaviour, including suicidal orientation of thoughts or actions (See Section “Peculiarities of Application”).

On nervous system:

Not often: dizziness, headache, drowsiness.

Rarely: convulsions, tremor, paresthesia.

Very rarely: sensory or sensorimotor peripheral neuropathy, dysgeusia (subjective taste disorder), including ageusia (loss of taste), parosmia (flair disorder), including anosmia (absence of flair).

On organs of vision

Very rarely: visual disorders.

On organs of hearing and ear labyrinth

Not often: vertigo.

Very rarely: hearing impairment.

Unknown occurrence: ringing in the ears.

Cardiac impairment

Rarely: tachycardia.

Unknown: prolongation of Q-T interval on ECG (See Section “Peculiarities of Application” (prolongation of Q-T interval), and Section “Overdosage”).

Vascular disorders

Rarely: hypotension.

Respiratory, chest and mediastinal disorders

Rarely: bronchospasms, dyspnoea.

Very rarely: allergic pneumonitis.

On gastrointestinal tract

Often: diarrhoea, nausea.

No often: vomiting, abdominal pain, dyspepsia, abdominal swelling, constipation.

Rarely: haemorrhagic diarrhoea, which in very rare cases may indicate the enterocolitis, including pseudomembranous colitis.

Hepatobiliary disorders

Often: increase in values of hepatic enzymes (ALT/AST, alkaline phosphatase, GGTP).

Not often: increase in bilirubin in blood.

Very rarely: hepatitis.

Unknown: reports of jaundice and severe liver damage, including cases of acute liver impairment in course of levofloxacin taking mainly in patients with severe underlying diseases (See Section “Peculiarities of Application”).

On skin and hypodermic tissues

Not often: rash, itching.

Rarely: urticaria.

Very rarely: angioneurotic oedema, hypersensitivity to solar and ultraviolet radiation.

Unknown occurrence: toxic epidermal necrolysis (Lyell’s syndrome), Stevens-Johnson syndrome, exudative erythema multiforme, hyperhidrosis.

Mucocutaneous reactions may sometimes occur even after taking of the first dose.

On musculoskeletal system

Rarely: tendons injury (See Section “Peculiarities of Application”), including their inflammation (tendinitis) (e.g., Achilles tendon inflammation), arthralgia, myalgia.

Very rarely: tendon rupture (See Section “Peculiarities of Application”). This unwanted side effect may occur within 48 hours after the beginning of treatment and affect Achilles tendon of both legs. There is a possibility of muscle weakness which may be especially significant to patients with myasthenia gravis.

Unknown: muscular system damage (rhabdomyolysis).

 

On kidneys and urinary system

Not often: increased values of creatinine in blood serum.

Very rarely: acute renal impairment (e.g., as a result of interstitial nephritis).

General disorders and conditions at points of drug introduction

Not often: asthenia.

Very rarely: pyrexia.

Unknown: pain (including pain in back, chest, and limbs).

Other unwanted side effects associated with fluoroquinolone application are as follows:

  • extrapyramidal symptoms and other disorders of coordination of movements;
  • hypersensitive vasculitis;
  • porphyria attacks in patients with porphyria.

Overdosage. Main predictable symptoms of Levobax overdosage concern the central nervous system (dizziness, impairment of consciousness, and convulsive attacks) and reactions from gastrointestinal tract (nausea, erosion of mucous membranes). According to the results of studies, in case of taking of doses higher than therapeutic ones the prolongation of Q-T interval is observed. In case of overdosage the patient requires thorough observation, including ECG.

Treatment is symptomatic. In case of severe overdose, gastric lavage is prescribed. In order to protect mucous coat of stomach antacid agents are used.

Haemodialysis, including peritoneal dialysis or CAPD, is not effective for levofloxacin excretion. There are no specific antidotes.

 Application during Pregnancy and Breast-Feeding Periods. Due to absence of studies and possible damage of articular cartilage damage by quinolones in the growing organism, Levobax cannot be prescribed to pregnant or feeding women. If in course of treatment with Levobax the pregnancy is diagnosed, it is necessary to inform the doctor.

Children. Application of Levobax is contraindicated to children since damage of articular cartilage is possible.

Peculiarities of Application.

In case of severe pneumonia caused by pneumococci Levobax may not give the optimum therapeutic effect.

Hospital infections caused by P. aeruginosa may require combined therapy.

Tendinitis and rupture of tendons

Rarely cases of tendinitis may occur. The most frequently it concerns Achilles tendon and may result in its rupture. The risk of tendinitis and tendon rupture is increased in elderly patients and patients taking corticosteroids. Therefore, thorough observation of such patients is required in case of Levobax prescription. Patients should consult a doctor if they observe symptoms of tendinitis. In case of suspected tendinitis it is required to immediately stop the treatment with Levobax and start relevant treatment (e.g., to ensure tendon immobilization).

Diseases caused by Clostridium difficile

Diarrhoea, especially in severe cases, persistent and/or haemorrhagic, in course of or after the treatment with Levobax tablets may be the symptom of disease caused by Clostridium difficile, the most severe form of which is pseudomembranous colitis. In case of suspected pseudomembranous colitis it is required to immediately stop Levobax tablets taking, and the patients shall immediately be subject to treatment with supporting agents and specific therapy (e.g., orally taken vancomycin). Drugs that inhibit intestinal motility are contraindicated in such clinical situation.

Patients prone to convulsions

Levobax tablets are contraindicated to patients with epilepsy in past history, and, as in case of other quinolones, it should be applied with extreme care in patients inclined to convulsions, such as patients with previous damages of central nervous system; in case of simultaneous treatment with fenbufen and similar non-steroid anti-inflammatory agents or drugs that increase readiness for convulsions (decrease convulsive threshold), such as teofilin (See Section “Interaction with Other Drugs and Other Types of Interaction”). In case of convulsions the treatment with levofloxacin should be stopped.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or apparent defects of glucose-6-phosphate dehydrogenase activity may be prone to haemolytic reactions in course of treatment with antibacterial drugs of quinolone group, and, therefore, levofloxacin should be applied with care.

Patients with renal impairment

Since levofloxacin is mainly excreted by kidneys, adjustment of dose is required in patients with impaired renal function (renal insufficiency) (See Section “Method of Application and Dosage”).

Hypersensitivity reactions

Levofloxacin may sometimes cause serious potentially fatal hypersensitivity reactions (e.g., angioneurotic oedema up to anaphylactic shock) after application of the initial dose (See Section “Side Effects”). In such a case patients should immediately stop the treatment and turn to the doctor.

Hypoglycaemia

As in case with all quinolones, there are reports of hypoglycaemia cases, especially in patients with pancreatic diabetes who received concurrent treatment with hypoglycaemic agents orally (e.g., with glibenclamid or insulin). Careful observation of glucose levels in patients with pancreatic diabetes is recommended (See Section “Side Effects”).

Photosensitization Prevention

Although photosensitization occurs very rarely in course of levofloxacin taking, in order to prevent it patients are recommended not to subject themselves to intensive sun rays or artificial ultraviolet radiation (e.g., ultraviolet lamps, solarium) without any specific need.

Patients who received vitamin K antagonists

Due to possible increase in values of coagulation tests (PT/International normalization ratio) and/or bleeding in patients who received Levobax with vitamin K antagonists (e.g., warfarin), coagulation tests should be observed in case of simultaneous application of these drugs (See Section “Interaction with Other Drugs and Other Types of Interaction”).

Psychotic Reactions

There have been reports of psychotic reactions in patients taking quinolones, including levofloxacin. In very rare cases these reactions progressed to suicidal thoughts and self-destructing behaviour, sometimes after taking of one dose of levofloxacin only (See Section “Side Effects”). In case of such symptoms it is necessary to stop treatment with levofloxacin and take appropriate measures. It is recommended to apply with care levofloxacin in patients with psychotic disorders or patients with mental diseases in past history.

Prolongation of Q-T Interval

Fluoroquinolones, including levofloxacin, should be carefully applied in patients with such known factors of risk of prolongation of Q-T interval as:

-       congenital syndrome of prolongation of Q-T interval;

-       concurrent application of drugs known for their ability to prolong Q-T interval (e.g., antiarrhythmic drugs of IA and III class, tricyclic antidepressants, macrolides);

-       uncompensated electrolytic imbalance (e.g., hypokaliemia, hypomagnesemia);

-       in elderly patients;

-       heart disease (e.g., impaired cardiac function, myocardial infarction, bradycardia) (See Sections “Method of Application and Dosage” (Elderly Patients), (“Interaction with Other Drugs and Other Types of Interaction”, “Side Effects”, “Overdosage”).

Peripheral Neuropathy

There have been reports of rapidly-arising sensor and sensorimotor peripheral neuropathy in patients that were taking fluoroquinolones, including levofloxacin. Taking of levofloxacin should be stopped if patient demonstrates symptoms of neuropathy in order to prevent irreversible condition.

Opiates

Opiates may be mistakenly determined in urine of patients that were taking levofloxacin. There may appear a need to confirm the positive results for opiates by means of more specific methods.

Hepatobiliary Disorders

There have been reports of cases of hepatic necrosis, even liver impairment threatening the life of patient in course of levofloxacin application, mainly in patients with such severe underlying diseases as sepsis, for instance (See Section “Side Effects”). Patients are recommended to stop the treatment and turn to the doctor in case of the following symptoms of liver disease: anorexia, jaundice, dark urine, itching or abdominal pain.

Ability to Affect the Rate of Reactions when Driving or Operating Other Mechanisms.

Patients that drive transport vehicles or operate machines and mechanisms should take into account possible unwanted effects on nervous system (dizziness, stiffness, drowsiness, mental confusion, visual and hearing disorders, disorder of the process of movement, including when walking).

Interaction with Other Drugs and Other Types of Interaction.

Other drugs influence on Levobax.

Iron salts, antacids containing magnesium and aluminium

Absorption of levofloxacin is significantly decreased in case of simultaneous application of Levobax tablets with iron salts and antacids containing magnesium or aluminium. Levobax tablets should be taken 2 hours before or 2 hours after taking of drugs containing bivalent or trivalent cations such as iron salts or antacids that contain magnesium or aluminium (See Section “Method of Application and Dosage”). No interaction with calcium carbonate has been detected.

 Sucralfate

Bioavailability of Levobax tablets is significantly decreased in case the drug is applied simultaneously with sucralfate. If the patient needs to take both sucralfate and Levobax, it is recommended to take sucralfate 2 hours after taking Levobax (See Section “Method of Application and Dosage”).

Teofilin, fenbufen or similar non-steroid anti-inflammatory drugs

No pharmacokinetic interaction of levofloxacin with Teofilin has been detected. However, there is a possibility of significant decrease in convulsive threshold in case of simultaneous application of quinolones with teofilin, non-steroid anti-inflammatory drugs and other agents that reduce convulsive threshold. Concentration of levofloxacin in presence of fenbufen was approximately 13% higher than in case of taking of levofloxacin only.

Probenecid and cimetidine

Probenecid and cimetidine statistically surely influence excretion of levofloxacin. Renal clearance of levofloxacin is reduced in presence of cimetidine by 24% and probenecid by 34%.  That is because both drugs are able to block tubular secretion of levofloxacin. However, in case of doses tested in course of study, it is not likely that statistically significant kinetic differences could have clinical significance. Care should be taken in case of simultaneous taking of levofloxacin with drugs that influence tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other information

The studies of clinical pharmacology showed that simultaneous application of levofloxacin and such drugs as calcium carbonate, digoxin, glibenclamid, and ranitidine demonstrated no clinically significant effect on pharmacokinetics of levofloxacin.

Influence of Levobax on Other Drugs

Cyclosporine

In case of simultaneous application with levofloxacin the half-excretion period of cyclosporine is increased by 33%.

Vitamin K Antagonists

In case of simultaneous application with vitamin K antagonists (e.g., warfarin) there have been reports of increase in values of coagulation tests (PT/International normalization ratio) and bleeding occurrence. Taking this into account, it is required to observe coagulation indices in patients simultaneously receiving vitamin K antagonists (See Section “Peculiarities of Application”).

Drugs prolonging Q-T interval

Similarly to other fluoroquinolones, Levofloxacin should be carefully applied in patients receiving other drugs known for their ability to prolong Q-T interval (e.g., antiarrhythmic drugs of IA and III class, tricyclic antidepressants, and macrolides). (See Section “Peculiarities of Application”).

Other Types of Interaction

Food intake

No clinically significant interaction with food products has been observed. Therefore, Levobax may be taken irrespective of meals.

It is not recommended to take Levobax with alcohol.

Pharmacological Properties

Pharmacodynamics. Levofloxacin is a synthetic antibacterial drug of fluoroquinolone group, is S-enantiomer of racemic mixture of Ofloxacin drug.

Mechanism of Action.

As an antibacterial drug of fluoroquinolone group, levofloxacin acts on DNA-DNA-gyrase complex and topoisomerase IV.

Pharmacokinetics/Pharmacodynamics Ratio

Degree of bacterial activity of levofloxacin depends on relation between maximum concentration in blood serum (Cmax) or area under pharmacokinetic curve “concentration–time” (AUC) and minimum inhibitory concentration (MIC).

 

Mechanism of Resistance

Basic resistance mechanism is the result of mutation in gyr-A genes. In vitro there is cross-resistance between levofloxacin and other fluoroquinolones.

Thanks to the mechanism of action usually there is no cross-resistance between levofloxacin and other categories of antibacterial drugs.

Limiting Values

Recommended by the European Union Committee for Antimicrobial Susceptibility Testing (EUCAST) MIC limiting values for levofloxacin that separate susceptible microorganisms from organisms of intermediate susceptibility (moderately-resistant), and organisms of intermediate susceptibility from resistant organisms are represented in MIC (mg/l) testing table below:

Clinical limiting values of MIC (according to EUCAST) for levofloxacin (20.06.2006):

Pathogen Susceptible Resistant
Enterobacteriacae ≤ 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 ≤ 2 mg/l > 2 mg/l
Streptococcus A, B, C, G ≤ 1 mg/l > 2 mg/l
H. influenza

M. catarrhalis2≤ 1 mg/l> 1 mg/lLimiting values not connected with species3≤ 1 mg/l> 2 mg/l1 Limiting value of MIC between susceptible and intermediate (moderately resistant) strains was increased from 1.0 to 2.0 in order to restrain growth of wild strains of this microorganism which demonstrate variability of this parameter. Limiting values concern high-dosage therapy.

2 Strains with MIC values higher than the limiting value between susceptible and intermediate (moderately-resistant) strains are very rare, or have not been reported of. Tests for identification and antimicrobial susceptibility on any such isolate should be repeated, and if the result is confirmed, such isolate should be sent to reference laboratory.

3 MIC limiting values not connected with species were determined mainly on the basis of pharmacokinetics/pharmacodynamics data; they are independent of distribution of MIC of certain species. They should be used only for the species for which the limiting values typical of species have not been determined; and should not be used for species in which testing for susceptibility is not recommended or for which there is no sufficient evidence in respect of doubtful species (Enterococcus, Neisseria, gram-negative anaerobes).

 

Recommended limiting values of MIC for levofloxacin which separate susceptible organisms from intermediate ones, and intermediate organisms from resistant organisms are represented in the table below, for testing of MIC (mcg/ml) or disc diffusion method (diameter of area [mm] using disc with levofloxacin 5 mcg).

Recommended by CLSI limiting values of MIC and disc diffusion method for levofloxacin (M100-S17, 2007):

Pathogen Susceptible Resistant
Enterobacteriacae ≤ 2 mcg/ml

≥ 17 mm≥ 8 mcg/ml

≤ 13 mmNot Enterobacteriacae≤ 2 mcg/ml

≥ 17 mm≥ 8 mcg/ml

≤ 13 mmAcinetobacter spp.≤ 2 mcg/ml

≥ 17 mm≥ 8 mcg/ml

≤ 13 mmStenotrophomonas maltophilia≤ 2 mcg/ml

≥ 17 mm≥ 8 mcg/ml

≤ 13 mmStaphylococcus spp.≤ 1 mcg/ml

≥ 19 mm≥ 4 mcg/ml

≤ 15 mmEnterococcus spp.≤ 2 mcg/ml

≥ 17 mm≥ 8 mcg/ml

≤ 13 mmH. influenzae

M. catarrhalis1≤ 2 mcg/ml

≥ 17 mm Streptococcus pneumoniae≤ 2 mcg/ml

≥ 17 mm≥ 8 mcg/ml

≤ 13 mmBeta-haemolytic

Streptococcus≤ 2 mcg/ml

≥ 17 mm≥ 8 mcg/ml

≤ 13 mm1 Absence or rare occurrence of resistant strains preliminarily excludes determination of any other categories of results except for “susceptible ones”. For strains that give results indicating “non-susceptible” category, identification of organisms and results of tests for antimicrobial susceptibility should be confirmed by reference laboratory using CLSI reference method of dilution.

 

Antibacterial range

Occurrence of resistance may vary geographically and in time for selected species, therefore, it is desirable to obtain local data concerning resistance, especially in course of treatment of severe infections. In case of necessity it is required to seek advice of an expert, if the local occurrence of resistance is such that the efficiency of agent is doubtful at least in respect of some types of infections.

Usually susceptible species

Aerobic gram-positive bacteria

methicillin-resistant Staphylococcus aureus*, Staphylococcus saprophyticus, Streptococci, groups C and G, Streptococcus agalactiae, Streptococcus pneumoniae*, Streptococcus pyogenes*.

 

Aerobic gram-negative bacteria

Burkholderia cepacia**, Eikenella corrodens, Haemophilus influenzae*, Haemophilus para-influenzae*, Klebsiella oxytoca, Klebsiella pneumoniae*, Moraxella catarrhalis*, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri.

 

Anaerobic bacteria

Peptostreptococcus.

 

Other

Chlamydophila pneumoniae*, Chlamydophila psittaci, Chlamidia trachomatis, Legionella pneumophila*, Mycoplasma pneumoniae*, Mycoplasma hominis, Ureoplasma urealyticum.

 

 

Species for which acquired (secondary) resistance may be problematic

Aerobic gram-positive bacteria

Enterococcus faecalis*, methicillin-resistant Staphylococcus aureus, Staphylococcus coagulase spp.

 

Aerobic gram-negative bacteria

Acinetobacter baumannii*, Citrobacter freundii*, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae*, Escherichia coli*, Morganella morganii*, Proteus mirabilis*, Providencia stuartii, Pseudomonas aeruginosa*, Serratia marcescens*.

 

Anaerobic bacteria

Bacteroides fragilis, Bacteroides ovatus**, Bacteroides thataiotamicron**, Bacteroides vulgatus**, Clostridium difficile**.

 

 

* Clinical efficiency was demonstrated for susceptible isolates in approved clinical indications.

** Natural intermediate susceptibility.

Other data

Hospital infection caused by P. aeruginosa may require combined therapy.

Pharmacokinetics

Absorption

When taken orally levofloxacin is rapidly and almost completely absorbed, meanwhile peak concentrations in blood plasma are reached within an hour. Absolute bioavailability is about 100%.

Distribution

Approximately 30-40% of levofloxacin is bound with blood serum protein.  Cumulative effect of levofloxacin when taken in dose of 500 mg once a day is almost absent. There is insignificant but predictable cumulative effect after taking of 500 mg doses twice a day.  Stable condition is reached within 3 days.

Penetration into tissues and body fluids

Penetration into bronchial mucous membrane, lung tissues bronchial secretion (LTBS)

Maximum concentration of levofloxacin in bronchial mucous membrane and lungs bronchial secretion after oral taking of 500 mg was 8.3 mcg/g and 10.8 mcg/g, respectively. These values were reached within an hour after drug taking.

Penetration into lungs tissues

Maximum concentrations of levofloxacin in lungs tissues after oral taking of 500 mg were about 11.3 mcg/g and were reached in 4-6 hours after drug taking. Concentration in lungs exceeds the same in blood plasma.

Penetration into bladder contents

Maximum concentrations of levofloxacin of 4.0-6.7 mcg/ml in bladder content were reached in 2-4 hours after drug taking after 3 days of treatment with doses of 500 mg once or twice per day, respectively.

Penetration into cerebrospinal fluid

Levofloxacin poorly penetrates into cerebrospinal fluid.

Penetration into prostate tissues

After oral taking of 500 mg of levofloxacin once a day during 3 days the average concentrations in prostate tissues were reaching 8.7 mcg/g, 8.2 mcg/g and 2.0 mcg/g in 2 hours, 6 hours and 24 hours, respectively; the average prostate/plasma concentrations ratio was 1.84.

Concentration in urine

Average concentration in urine in 8-12 hours after single doses of 150 mg, 300 mg or 500mg of levofloxacin taken orally was 44 mg/l, 91 mg/l and 200 mg/l, respectively.

Biotransformation

Levofloxacin is very slightly metabolized; the metabolites are desmethyl levofloxacin and levofloxacin N-oxide. These metabolites stand for less than 5% of drug amount excreted with urine. Levofloxacin is stereochemically stable and is not subject to inversion of chiral structure.

Excretion

After oral or intravenous introduction levofloxacin is slowly excreted from blood plasma (half-excretion period is 6-8 hours). It is usually excreted by kidneys (over 85% of the dose introduced).

There is no significant difference in levofloxacin pharmacokinetics after intravenous or oral introduction, which indicates that these ways (oral and intravenous) are interchangeable.

Linearity

Levofloxacin follows linear pharmacokinetics within the range of 50-600 mg.

Patients with impaired renal function

Pharmacokinetics of levofloxacin is influenced by renal impairment. In case of diminished renal function the renal excretion and clearance are decreased, and the periods of half-excretion are increased, which is presented in table below:

Creatinine clearance

(ml/min)< 2020-4050-80Renal clearance

(ml/min)132657Half-excretion period

(hours)35279

 

Elderly patients

There is no significant difference in levofloxacin pharmacokinetics in young and elderly patients except for differences connected with creatinine clearance.

Gender differences

There is no evidence that these gender differences are clinically significant.

Pharmaceutical Characteristics.

Main Physicochemical Properties: tablets of white to light-beige colour in shape of caplets coated with membrane.

Effective Period.

3 years.

Storage Conditions.

Store under the temperature below 25°C out of reach of children.

Packaging.

7 tablets in blister, 1 blister in carton box.

Category of Selling.

On prescription.

Manufacturer.

Bioveeta Laboratories Pvt. Ltd.

Location.

India, B705, Vardhaman vatika, G.B. Road, Manpada, Thane (W).

Date of Last Revision.