Levofloxacin Ekolevid® tablets 250 mg

Instructions for use of Levofloxacin Ekolevid® tablets 250 mg

Trade name of the drug: Levofloxacin Ekolevid^®

International nonproprietary name: levofloxacin

Dosage form: film-coated tablets

Composition per one tablet:

Description

Capsule-shaped, biconvex, film-coated tablets, white or almost white; a cross-section shows two layers, the inner layer is from light yellow to yellow in color, white specks are allowed.

Pharmacotherapeutic group: antimicrobial agent, fluoroquinolone.

ATC code: J01MA12.

Pharmacological properties

Pharmacodynamics

Levofloxacin is a synthetic broad-spectrum antibacterial drug from the fluoroquinolone group, containing the levorotatory isomer of ofloxacin as the active substance.

Levofloxacin blocks DNA gyrase, disrupts DNA supercoiling and cross-linking of breaks, inhibits DNA synthesis, causes profound morphological changes in the cytoplasm, cell wall and membranes of bacteria.

Levofloxacin acts bactericidally and is active against a large number of bacterial pathogens both in vitro and in vivo.

Sensitive microorganisms (Minimum Inhibitory Concentration (MIC) ≤ 2 mg/L):

• Aerobic Gram-positive microorganisms: Bacillus anthracis, Corynebacterium diphtheriae, Corynebacterium jeikeium, Enterococcus spp., including Enterococcus faecalis, Listeria monocytogenes, Staphylococcus spp. (coagulase-negative, methicillin-sensitive / leukotoxin-producing / moderately sensitive strains), including Staphylococcus aureus (methicillin-sensitive strains), Staphylococcus epidermidis (methicillin-sensitive strains), Streptococcus spp. groups C and G, Streptococcus agalactiae, Streptococcus pneumoniae (penicillin-sensitive / moderately sensitive / resistant strains), Streptococcus pyogenes, Streptococcus spp. Viridans group (penicillin-sensitive / resistant strains).
• Aerobic Gram-negative microorganisms: Acinetobacter spp., including Acinetobacter baumannii, Actinobacillus actinomycetemcomitans, Citrobacter freundii, Eikenella corrodens, Enterobacter spp., including Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae (ampicillin-sensitive / resistant strains), Haemophilus parainfluenzae, Helicobacter pylori, Klebsiella spp., including Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis (beta-lactamase producing and non-producing strains), Morganella morganii, Neisseria gonorrhoeae (penicillinase-producing and non-producing strains), Neisseria meningitidis, Pasteurella spp., including Pasteurella canis, Pasteurella dagmatis, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Providencia spp., including Providencia rettgeri, Providencia stuartii, Pseudomonas spp., including Pseudomonas aeruginosa (hospital-acquired infections caused by Pseudomonas aeruginosa may require combination therapy), Serratia spp., including Serratia marcescens, Salmonella spp.
• Anaerobic microorganisms: Bacteroides fragilis, Bifidobacterium spp., Clostridium perfringens, Fusobacterium spp., Peptostreptococcus spp., Propionibacterium spp., Veillonella spp.
• Other microorganisms: Bartonella spp., Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia trachomatis, Legionella pneumophila, Legionella spp., Mycobacterium spp., including Mycobacterium leprae, Mycobacterium tuberculosis, Mycoplasma hominis, Mycoplasma pneumoniae, Rickettsia spp., Ureaplasma urealyticum.

Moderately sensitive microorganisms (MIC = 4 mg/L):

• Aerobic Gram-positive microorganisms: Corynebacterium urealyticum, Corynebacterium xerosis, Enterococcus faecium, Staphylococcus epidermidis (methicillin-resistant strains), Staphylococcus haemolyticus (methicillin-resistant strains).
• Aerobic Gram-negative microorganisms: Campylobacter jejuni, Campylobacter coli.
• Anaerobic microorganisms: Prevotella spp., Porphyromonas spp.

Resistant microorganisms (MIC > 8 mg/L):

• Aerobic Gram-positive microorganisms: Staphylococcus aureus (methicillin-resistant strains), other Staphylococcus spp. (coagulase-negative methicillin-resistant strains).
• Aerobic Gram-negative microorganisms: Alcaligenes xylosoxidans.
• Anaerobic microorganisms: Bacteroides thetaiotaomicron
• Other microorganisms: Mycobacterium avium.

Clinical efficacy (efficacy in clinical studies for infections caused by the following microorganisms):

• Aerobic Gram-positive microorganisms: Enterococcus faecalis, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes.
• Aerobic Gram-negative microorganisms: Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Morganella morganii, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens.
• Other microorganisms: Chlamydia pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae.

Resistance to levofloxacin develops through a stepwise process of mutations in the genes encoding both type II topoisomerases: DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as microbial cell penetration barriers (a mechanism characteristic of Pseudomonas aeruginosa) and efflux mechanisms (active removal of the antimicrobial agent from the microbial cell), can also reduce the sensitivity of microorganisms to levofloxacin.

Due to the specific mechanism of action of levofloxacin, cross-resistance between levofloxacin and other antimicrobial agents is usually not observed.

Pharmacokinetics

Absorption

Levofloxacin is rapidly and almost completely absorbed after oral administration; food intake has little effect on its absorption. The absolute bioavailability after oral administration is 99-100%. After a single 500 mg dose of levofloxacin, the maximum plasma concentration (Cmax) is reached within 1-2 hours and is 5.2±1.2 µg/ml. The pharmacokinetics of levofloxacin are linear in the dose range of 50 to 1000 mg. Steady-state plasma concentrations of levofloxacin are achieved within 48 hours when taking 500 mg of levofloxacin once or twice daily.

On day 10 of oral administration of Levofloxacin Ekolevid® 500 mg once daily, the Cmax of levofloxacin was 5.7±1.4 µg/ml, and the minimum concentration of levofloxacin (trough concentration before the next dose) (Cmin) in plasma was 0.5±0.2 µg/ml.

On day 10 of oral administration of Levofloxacin Ekolevid® 500 mg twice daily, the Cmax was 7.8±1.1 µg/ml, and the Cmin was 3.0±0.9 µg/ml.

Distribution

Protein binding with serum proteins is 30-40%. After single and repeated administration of 500 mg levofloxacin, the volume of distribution of levofloxacin averages 100 L, indicating good penetration of levofloxacin into the organs and tissues of the human body.

Penetration into bronchial mucosa, epithelial lining fluid, alveolar macrophages

After a single oral dose of 500 mg levofloxacin, maximum concentrations in the bronchial mucosa and epithelial lining fluid were reached within 1 hour or 4 hours and were 8.3 µg/g and 10.8 µg/ml, respectively, with penetration ratios (compared to plasma concentration) of 1.1-1.8 and 0.8-3.0, respectively. After 5 days of oral administration of 500 mg levofloxacin, mean concentrations 4 hours after the last dose in epithelial lining fluid were 9.94 µg/ml and in alveolar macrophages were 97.9 µg/ml.

Penetration into lung tissue

Maximum concentrations in lung tissue after a single oral dose of 500 mg levofloxacin were approximately 11.3 µg/g and were reached 4-6 hours after administration, with penetration ratios of 2-5 compared to plasma concentration.

Penetration into alveolar fluid

After 3 days of taking 500 mg levofloxacin once or twice daily, maximum concentrations in alveolar fluid were reached 2-4 hours after administration and were 4.0 and 6.7 µg/ml, respectively, with a penetration ratio of 1 compared to plasma concentrations.

Penetration into bone tissue

Levofloxacin penetrates well into cortical and cancellous bone tissue in both proximal and distal parts of the femur, with a penetration ratio (bone tissue/plasma) of 0.1-3. Maximum concentrations of levofloxacin in cancellous bone tissue of the proximal femur after a single 500 mg oral dose were approximately 15.1 µg/g (2 hours after administration).

Penetration into cerebrospinal fluid

Levofloxacin penetrates poorly into cerebrospinal fluid.

Penetration into prostate tissue

After oral administration of 500 mg levofloxacin once daily for 3 days, the mean concentration of levofloxacin in prostate tissue was 8.7 µg/g, and the mean prostate/plasma concentration ratio was 1.84.

Urine concentrations

Mean urine concentrations 8-12 hours after oral doses of 150, 300, and 600 mg levofloxacin were 44 µg/ml, 91 µg/ml, and 162 µg/ml, respectively.

Metabolism

Levofloxacin is metabolized to a small extent (5% of the administered dose). Its metabolites are desmethyl-levofloxacin and levofloxacin N-oxide, which are excreted by the kidneys. Levofloxacin is stereochemically stable and does not undergo chiral conversion.

Excretion

After oral administration, levofloxacin is eliminated from plasma relatively slowly (half-life (T1/2) - 6-8 hours). Excretion is primarily renal (more than 85% of the administered dose). The total clearance of levofloxacin after a single 500 mg dose was 175±29.2 ml/min.

There are no significant differences in the pharmacokinetics of levofloxacin between intravenous and oral administration, confirming that oral and intravenous administration are interchangeable.

Pharmacokinetics in specific patient groups

The pharmacokinetics of levofloxacin do not differ between men and women.

The pharmacokinetics in elderly patients do not differ from those in young patients, except for differences associated with variations in creatinine clearance (CrCl).

In renal impairment, the pharmacokinetics of levofloxacin are altered. As renal function deteriorates, renal excretion and renal clearance (CLR) decrease, and T1/2 increases.

Pharmacokinetics in renal impairment after a single oral dose of 500 mg of Levofloxacin Ekolevid®.

Indications for use

Treatment of infectious and inflammatory diseases caused by microorganisms sensitive to levofloxacin:

• Community-acquired pneumonia;
• Complicated urinary tract infections and pyelonephritis;
• Chronic bacterial prostatitis;
• Skin and soft tissue infections;
• For the complex treatment of drug-resistant forms of tuberculosis;
• Prevention and treatment of anthrax by inhalation.

For the treatment of the following infectious and inflammatory diseases, levofloxacin may be used as an alternative to other antimicrobial drugs:

• Acute sinusitis;
• Exacerbation of chronic bronchitis;
• Uncomplicated cystitis.

When using Levofloxacin Ekolevid®, official national recommendations on the appropriate use of antibacterial drugs, as well as the sensitivity of pathogens in a particular country, should be taken into account (see section "Special Instructions").

Contraindications

Hypersensitivity to levofloxacin, other fluoroquinolones, or any component of the drug; epilepsy; tendon damage during previous treatment with quinolones; pregnancy; breastfeeding; children and adolescents (under 18 years of age); myasthenia gravis.

Lactose intolerance or lactase deficiency, as well as glucose-galactose malabsorption.

Due to the inability to split the tablet, the use of the drug is contraindicated in patients with renal impairment:

• In patients with creatinine clearance less than 50 ml/min, use is impossible for the dosing regimen with an initial dose of 250 mg/24 h;
• In patients with creatinine clearance less than 20 ml/min, use is impossible for the dosing regimen with initial doses of 500 mg/24 h and 500 mg/12 h;
• With creatinine clearance less than 10 ml/min (including during hemodialysis and continuous ambulatory peritoneal dialysis), use is impossible for all dosing regimens.

With caution

• In patients predisposed to seizures [in patients with previous central nervous system (CNS) disorders; in patients concurrently taking drugs that lower the seizure threshold of the brain, such as fenbufen, theophylline] (see section "Drug Interactions");
• In patients with latent or manifested glucose-6-phosphate dehydrogenase deficiency (increased risk of hemolytic reactions during treatment with quinolones);
• In patients with impaired renal function (mandatory monitoring of renal function and dose adjustment is required, see section "Dosage and Administration");
• In patients with known risk factors for QT interval prolongation: elderly patients; female patients; patients with uncorrected electrolyte disturbances (with hypokalemia, hypomagnesemia); with congenital long QT syndrome; with heart disease (heart failure, myocardial infarction, bradycardia); when taking drugs that can prolong the QT interval (class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) (see sections "Overdose", "Drug Interactions", "Special Instructions");
• In patients with diabetes mellitus receiving oral hypoglycemic drugs (e.g., glibenclamide) or insulin preparations (increased risk of hypoglycemia);
• In patients with severe adverse reactions to other fluoroquinolones, such as severe neurological reactions (increased risk of similar adverse reactions when using levofloxacin);
• In patients with psychosis or with a history of mental illness (see section "Special Instructions");
• In elderly patients, patients after transplantation, as well as with concomitant use of glucocorticosteroids (increased risk of tendinitis and tendon rupture) (see section "Special Instructions").

Use during pregnancy and breastfeeding

Levofloxacin is contraindicated for use in pregnant and breastfeeding women.

Dosage and administration

Orally. Once or twice daily. The tablets should be swallowed without chewing and washed down with a sufficient amount of liquid (from 0.5 to 1 glass).

The drug can be taken before meals or at any time between meals, as food intake does not affect the absorption of the drug (see section "Pharmacokinetics").

The drug should be taken at least 2 hours before or 2 hours after taking preparations containing magnesium and/or aluminum, iron, zinc, or sucralfate (see section "Drug Interactions").

Given that the bioavailability of levofloxacin when taking Levofloxacin Ekolevid® tablets is 99-100%, when switching a patient from intravenous infusion with other levofloxacin preparations, Levofloxacin Ekolevid® tablets should be continued at the same dose that was used during intravenous infusion of levofloxacin preparations (see section "Pharmacokinetics").

Missing one or more doses

If a dose is accidentally missed, the next dose should be taken as soon as possible, and then continue taking Levofloxacin Ekolevid® according to the recommended dosing regimen.

Dosage forms

Film-coated tablets, 250 mg and 500 mg.

5, 7, or 10 tablets in a blister strip made of polyvinyl chloride film and printed lacquered aluminum foil.

1 or 2 blister packs together with the instructions for use are placed in a cardboard carton.

Storage conditions

In a dry place, protected from light, at a temperature not exceeding 25 °C. Keep out of reach of children.

Shelf life

2 years. Do not use after the expiration date.

Prescription status

Dispensed by prescription.

Name and address of the legal entity in whose name the registration certificate is issued / Organization accepting claims:

JSC "AVVA RUS",

Russia, 121614, Moscow, Krylatskie Kholmy st., 30, building 9.

Tel./Fax: +7 (495) 956-75-54.

avva.com.ru

ecoantibiotic.ru

Production site address:

JSC "AVVA RUS",

Russia, 610044, Kirov region, Kirov, Luganskaya st., 53a.

Tel.: +7 (8332) 25-12-29; +7 (495) 956-75-54.

 The full instructions can be found in the "Instructions" file.