Levofloxacin, 500 mg 5 pcs

Pharmacotherapeutic group:

An antimicrobial agent, fluoroquinolone.

ATX code:

J01MA12

Pharmacological properties

Pharmacodynamics

Levofloxacin is a synthetic broad-spectrum antibacterial drug from the group of fluoroquinolones, containing levofloxacin, the left-handed isomer of ofloxacin, as an active substance. Levofloxacin blocks DNA-enzyme and topoisomerase IV, breaks supercoiling and cross-linking of DNA breaks, inhibits DNA synthesis and causes deep morphological changes in cytoplasm, cell wall and membranes of microbial cells.

Levofloxacin is active against most strains of microorganisms under both in vitro and in vivo conditions.

Sensitive microorganisms (MPC ≤2 mg/L, zone of inhibition >17 mm)

• aerobic gram-positive microorganisms: Bacillus anthracis, Corynebacterium diphtheriae, Corynebacterium jeikeium, Enterococcus spp. (including. Enterococcus faecalis), Listeria monocytogenes, Staphylococcus coagulase-negative methi-S(I) [coagulase-negative, methicillin-sensitive/ moderately sensitive], Staphylococcus aureus methi-S (methicillin-sensitive), Staphylococcus epidermidis methi-S (methicillin-sensitive), Staphylococcus spp. CNS (coagulazonegative), Streptococci group C and G, Streptococcus agalactiae, Streptococcus pneumoniae peni I/S/R (penicillin-moderately sensitive/sensitive/resistant), Streptococcus pyogenes, Viridans streptococci repi-S/R (penicillin-sensitive/resistant);
• aerobic Gram-negative microorganisms: Acinetobacter spp. (including Acinetobacter baumannii), Actinobacillus actinomycetemcomitans, Citrobacter freundii, Eikenella corrodens, Enterobacter aerogenes, Enterobacter spp. Enterobacler cloacae), Escherichia coli, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae ampi-S/R (ampicillin-sensitive/resistant), Haemophilus parainfluenzae, Helicobacter pylori, Klebsiella oxytoca, Klebsiella spp. (including Klebsiella pneumoniae, Klebsiella oxytoca), Moraxella catarrhalis /β+//β- (producing and non-producing beta-lactamases), Morganella morganii, Neisseria gonorrhoeae nonPPNG/PPNG (non-producing and producing penicillinase), Neisseria meningitidis, Pasteurella spp. Pasteurella multocida, Pasteurella dagmatis, Pasteurella canis), Proteus mirabilis, Proteus vulgaris, Providencia spp. (including Providencia rettgeri, Providencia Stuartii), Pseudomonas spp. (including Pseudomonas aeruginosa [hospital infections caused by Pseudomonas aeruginosa may require combined treatment]), Salmonella spp, Serratia spp. (including Serratia marcescens);
• anaerobic microorganisms: Bacteroides fragilis, Bifidobacterium spp., Clostridium perfringens, Fusobacterium spp., Peptostreptococcus, 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 susceptible microorganisms (MPC = 4 mg/l, inhibition zone 16-14 mm)

• aerobic gram-positive microorganisms: Corynebacterium urealyticum, Corynebacterium xerosis, Enterococcus faecium, Staphylococcus epidermidis methi-R (methicillin-resistant), Staphylococcus haemolyticus methi-R (methicillin-resistant);
• aerobic gram-negative bacteria: Campylobacter jejuni, Campylobacter coli;
• anaerobic microorganisms: Prevotella spp., Porphyromonas spp.

Levofloxacin-resistant microorganisms (MAC ≥8 mg/l, inhibition zone ≤13 mm)

• aerobic Gram-positive microorganisms: Staphylococcus aureus methi-R (methicillin-resistant), Staphylococcus coagulase-negative methi-R (coagulase-negative methicillin-resistant), Corynebacterium jeikeium;
• aerobic gram-negative microorganisms: Alcaligenes xylosoxidans;
• anaerobic microorganisms: Bacteroides thetaiotaomicron.

Other microorganisms: Mycobacterium avium.

Resistance

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

In view of the specific mechanism of action of levofloxacin there is usually no cross-resistance between levofloxacin and other antimicrobial agents.

Clinical efficacy (effectiveness in clinical studies in the treatment of 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 (Branhamella) catarrhalis, Morganella morganii, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens.
• Others: Chlamydia pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae.

Pharmacokinetics

Absorption

Levofloxacin is quickly and almost completely absorbed after oral administration; food has little effect on its absorption. Absolute bioavailability when administered orally is 99-100%. After a single use of 500 mg of levofloxacin maximum concentration (Cmax) in plasma is reached within 1-2 hours and is 5.2±1.2 µg/ml. Pharmacokinetics of levofloxacin is linear in dose range from 50 mg to 1000 mg. Equilibrium concentration of levofloxacin in plasma when 500 mg of levofloxacin is taken orally 1 or 2 times per day is reached within 48 hours.

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

On day 10 of oral levofloxacin 500 mg twice daily, the Cmax in plasma was 7.8±1.1 µg/ml and the Cmin was 3.0±0.9 µg/ml.

Distribution

The binding to serum proteins is 30-40%. After single and repeated oral administration of 500 mg of levofloxacin the volume of distribution of levofloxacin averaged 100 l, which indicates good penetration of levofloxacin into human organs and tissues.

Infiltration into the bronchial mucosa, epithelial lining fluid, alveolar macrophages

. After a single oral dose of 500 mg of levofloxacin, Cmax in bronchial mucosa and epithelial lining fluid were reached within 1 h or 4 h and were 8.3 µg/g and 10.8 µg/mL, respectively, with penetration rates in bronchial mucosa and epithelial lining fluid compared with plasma concentrations of 1.1-1.8 and 0.8-3.0, respectively.

After 5 days of oral administration of 500 mg of levofloxacin, mean concentrations of levofloxacin 4 hours after the last drug administration in the epithelial lining fluid were 9.94 µg/mL and in alveolar macrophages were 97.9 µg/mL.

Pulmonary tissue penetration

Cmax in pulmonary tissue after oral administration of 500 mg of levofloxacin was approximately 11.3 µg/g and was reached 4-6 h after drug administration with penetration ratios of 2.0-5.0 compared to plasma concentrations.

The penetration into alveolar fluid

. After 3 days of administration of 500 mg of levofloxacin 1 or 2 times daily, the Cmax of levofloxacin in alveolar fluid was reached 2-4 hours after drug administration and was 4.0 µg/ml and 6.7 µg/ml, respectively, with a penetration ratio of 1.0 compared to plasma concentrations.

Bone penetration

Levofloxacin penetrates well into cortical and cancellous bone tissue in both the proximal and distal femur, with a penetration ratio (bone tissue/plasma) of 0.1-3.0. Cmaxes of levofloxacin in the cancellous bone tissue of the proximal femur after oral administration of 500 mg of the drug were approximately 15.1 mcg/g (2 hours after drug administration).

Cerebrospinal fluid penetration

Levofloxacin poorly penetrates into the cerebrospinal fluid.

Permeasurement in prostate tissue

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

Urinary concentrations

The mean urinary concentrations 8-12 h after oral doses of 150 mg, 300 mg, and 600 mg of levofloxacin were 44 µg/ml, 91 µg/ml, and 162 µg/ml, respectively.

Metabolism

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

Levofloxacin is relatively slowly excreted from the blood plasma after oral administration (elimination half-life [T1/2] is 6-8 hours). Excretion is mainly by the kidneys (more than 85% of the administered dose). Total clearance of levofloxacin after a single dose of 500 mg was 175±29.2 ml/minute.

There are no significant differences in the pharmacokinetics of levofloxacin when administered intravenously and when administered orally, confirming that oral and intravenous administration are interchangeable.

Pharmacokinetics in selected patient groups

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

Pharmacokinetics in elderly patients does not differ from that in younger patients, except for differences in pharmacokinetics associated with differences in creatinine clearance (CK).

In renal failure, the pharmacokinetics of levofloxacin are altered. As renal function deteriorates, renal excretion and renal clearance (CIR) decreases and T1/2 is prolonged.

Pharmacokinetics in renal failure after a single oral dose of 500 mg of levofloxacin

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Indications

Treatment of infectious and inflammatory diseases caused by microorganisms sensitive to levofloxacin:
• complicated urinary tract infections and pyelonephritis;
• chronic bacterial prostatitis;
• for complex treatment of drug-resistant forms of tuberculosis;
• prevention and treatment of anthrax through airborne transmission.

For the treatment of the following infectious and inflammatory diseases, levofloxacin can only be used as an alternative to other antimicrobial drugs:
• community-acquired pneumonia;
• complicated infections of the skin and soft tissues;
• acute bacterial sinusitis;
• exacerbation of chronic bronchitis;
• uncomplicated cystitis.

When using the drug Levofloxacin, you should take into account official national recommendations for the proper use of antibacterial drugs, as well as the sensitivity of pathogenic microorganisms in a particular country (see section “Special instructions”).

Pharmacological effect

Pharmacotherapeutic group: systemic antibacterial agents; quinolone derivatives; fluoroquinolones.

ATX code: J01MA12

Pharmacological properties

Pharmacodynamics

Levofloxacin is a synthetic broad-spectrum antibacterial drug from the group of fluoroquinolones, a levorotatory isomer of ofloxacin.

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

Levofloxacin is active against most strains of microorganisms, both in vitro and in vivo.

Sensitive microorganisms (MIC ≤ 2 mg/l; inhibition zone ≥ 17 mm)

Aerobic gram-positive microorganisms:

Bacillus anthracis, Corynebacterium diphtheriae, Corynebacterium jeikeium, Enterococcus spp. (including Enterococcus faecalis), Listeria monocytogenes, Staphylococcus coagulase-negative methi-S(I) (coagulase-negative, methicillin-sensitive/moderately sensitive), Staphylococcus aureus methi-S (methicillin-sensitive), Staphylococcus epidermidis methi-S (methicillin-sensitive), Staphylococcus spp. CNS (coagulase-negative), Streptococci groups C and G, Streptococcus agalactiae, Streptococcus pneumoniae peni I/S/R (penicillin-moderately sensitive/-sensitive/-resistant), Streptococcus pyogenes, Viridans streptococci peni-S/R (penicillin-sensitive/-resistant).

Aerobic gram-negative microorganisms:

Acinetobacter spp. (including Acinetobacter baumannii), Actinobacillus actinomycetemcomitans, Citrobacter freundii, Eikenella corrodens, Enterobacter aerogenes, Enterobacter spp. (including Enterobacter cloacae), Escherichia coli, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae ampi-S/R (ampicillin-sensitive/-resistant), Haemophilus parainfluenzae, Helicobacter pylori, Klebsiella oxytoca, Klebsiella spp. (including Klebsiella pneumonia), Moraxella catarrhalis β+/β− (producing and non-producing beta-lactamases), Morganella morganii, Neisseria gonorrhoeae non PPNG/PPNG (non-producing and producing penicillinase), Neisseria meningitidis, Pasteurella spp. (including Pasteurella multocida, Pasteurella dagmatis, Pasteurella canis), Proteus mirabilis, Proteus vulgaris, Providencia spp. (including Providencia rettgeri, Providencia stuartii), Pseudomonas spp. (including Pseudomonas aeruginosa (hospital infections caused by Pseudomonas aeruginosa may require combination treatment), Salmonella spp., Serratia spp. (including Serratia marcescens).

Anaerobic microorganisms:

Bacteroides fragilis, Bifidobacterium spp., Clostridium perfringens, Fusobacterium spp., Peptostreptococcus, Propionibacterium spp., Veilonella spp.

Other microorganisms:

Bartonella spp., Chlamydia pneumoniae, Chlamydia psittaci, Chlamydia trachomatis, Legionella pneumophila, Legionella spp., Mycobacterium spp. (including Mycobacterium leprae, Micobacterium tuberculosis), Mycoplasma hominis, Mycoplasma pneumoniae, Ricketsia spp., Ureaplasma urealyticum.

Moderately sensitive microorganisms (MIC = 4 mg/l; inhibition zone
16-14 mm):

Aerobic gram-positive microorganisms:

Corynebacterium urealiticum, Corynebacterium xerosis, Enterococcus faecium, Staphylococcus epidermidis methi-R (methicillin-resistant), Staphylococcus haemolyticus methi-R (methicillin-resistant).

Aerobic gram-negative microorganisms:

Campilobacter jejuni, Campilobacter coli.

Anaerobic microorganisms:

Prevotella spp., Porphyromonas spp.

Levofloxacin-resistant microorganisms (MIC ≥ 8 mg/l; inhibition zone
≤ 13 mm):

Aerobic gram-positive microorganisms:

Staphylococcus aureus methi-R (methicillin-resistant), Staphylococcus coagulase-negative methi-R (coagulase-negative methicillin-resistant), Corynebacterium jeikeium.

Aerobic gram-negative microorganisms:

Alcaligenes xylosoxidans.

Anaerobic microorganisms:

Bacteroides thetaiotaomicron.

Other microorganisms:

Mycobacterium avium.

Resistance

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

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

Clinical efficacy (effectiveness in clinical studies in the treatment of 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 (Branhamella) catarrhalis, Morganella morganii, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens.

Other:

Chlamydia pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae.

Pharmacokinetics

Absorption

Levofloxacin is rapidly and almost completely absorbed after oral administration; food intake has little effect on its absorption. Absolute bioavailability when taken orally is 99-100%. After a single dose of 500 mg, the maximum concentration of levofloxacin in the blood plasma (Cmax) is reached within 1-2 hours and is 5.2 ± 1.2 μg/ml. The pharmacokinetics of levofloxacin is linear in the dose range from 50 to 1000 mg. The equilibrium concentration of levofloxacin in blood plasma when taken at a dose of 500 mg 1 or 2 times a day is achieved within 48 hours.

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

On the 10th day of oral administration of 500 mg levofloxacin 2 times a day, Cmax was
7.8 ± 1.1 μg/ml, and Cmin – 3.0 ± 0.9 μg/ml.

Distribution

Binding to serum proteins is 30-40%. After a single and repeated dose of 500 mg of levofloxacin, the volume of distribution of levofloxacin is, on average, 100 l, which indicates good penetration (penetration) of levofloxacin into organs and tissues of the human body.

Penetration into the bronchial mucosa, epithelial lining fluid, alveolar macrophages

After a single oral dose of 500 mg of levofloxacin, the Cmax of levofloxacin in the bronchial mucosa and epithelial lining fluid was achieved within
1 hour or 4 hours and was 8.3 μg/g and 10.8 μg/ml.

The penetration coefficients into the bronchial mucosa and the fluid of the epithelial lining, compared with the concentration in the blood plasma, are 1.1-1.8 and 0.8-3.0, respectively.

After 5 days of oral administration of 500 mg of levofloxacin, the average concentration of levofloxacin, 4 hours after the last dose, was 9.94 μg/ml in the fluid of the epithelial lining and 97.9 μg/ml in alveolar macrophages.

Penetration into lung tissue

Cmax in lung tissue after oral administration of 500 mg of levofloxacin was achieved after
4-6 hours and was approximately 11.3 μg/g with penetration coefficients of 2.0-5.0 compared to plasma concentrations.

Penetration into alveolar fluid

After 3 days of taking 500 mg of levofloxacin 1 or 2 times a day, the Cmax of levofloxacin in the alveolar fluid was achieved after 2-4 hours and was 4.0 and 6.7 mcg/ml, respectively, with a penetration coefficient of 1.0 compared with plasma concentrations.

Penetration into bone tissue

Levofloxacin penetrates well into cortical and cancellous bone tissue, both in the proximal and distal parts of the femur with a penetration coefficient (bone tissue/blood plasma) of 0.1-3.0. The Cmax of levofloxacin in cancellous bone tissue of the proximal femur after 500 mg oral administration was approximately 15.1 mcg/g (2 hours after administration of levofloxacin).

Penetration into the cerebrospinal fluid

Levofloxacin penetrates poorly into the cerebrospinal fluid.

Penetration into prostate tissue

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

Concentrations in urine

Mean urinary concentrations 8 to 12 hours after oral doses of 150, 300, and 600 mg of levofloxacin were 44 mcg/mL, 91 mcg/mL, and 162 mcg/mL, respectively.

Biotransformation

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

Elimination

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

The absence of significant differences in the pharmacokinetics of levofloxacin when administered intravenously and orally confirms the fact that oral administration and the intravenous route of administration are interchangeable.

Special patient groups

Floor

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

Elderly patients

Pharmacokinetics in elderly patients do not differ from those in younger patients, with the exception of differences in pharmacokinetics associated with changes in creatinine clearance (CC).

Patients with impaired renal function

In renal failure, the pharmacokinetics of levofloxacin changes. As renal function deteriorates, renal excretion and renal clearance (CIR) decrease and T1/2 increases.

Pharmacokinetics in renal failure after a single dose of 500 mg of levofloxacin:

CC (ml/min)

< 20

20-49

50-80

CIR (ml/min)

13

26

57

T1/2 (h)

35

27

9

Special instructions

Hospital-acquired infections caused by Pseudomonas aeruginosa may require combination treatment.

Risk of developing resistance

The prevalence of acquired resistance in cultured strains of microorganisms may vary by geographic region and over time. Therefore, country-specific information on levofloxacin resistance is required. For the treatment of severe infections or if treatment is ineffective, a microbiological diagnosis must be established with the isolation of the pathogen and determination of its sensitivity to levofloxacin.

Methicillin-resistant Staphylococcus aureus (Staphylococcus aureus)

There is a high likelihood that methicillin-resistant Staphylococcus aureus will be resistant to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of known or suspected infections caused by methicillin-resistant Staphylococcus aureus unless laboratory tests have confirmed the sensitivity of this microorganism to levofloxacin.

Disability and potential irreversible serious adverse reactions associated with fluoroquinolones

The use of fluoroquinolones, including levofloxacin, has been associated with disability and the development of irreversible serious adverse reactions from various body systems that can occur simultaneously in the same patient. Adverse reactions caused by fluoroquinolones include tendonitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and nervous system adverse reactions (hallucinations, anxiety, depression, insomnia, headaches, and confusion). These reactions may develop from several hours to several weeks after starting levofloxacin therapy. The development of these adverse reactions was observed in patients of any age or without the presence of previous risk factors. If the first signs or symptoms of any serious adverse reactions occur, use of levofloxacin should be discontinued immediately. Fluoroquinolones, including levofloxacin, should be avoided in patients who have experienced any of these serious adverse reactions.

Patients predisposed to developing seizures

Like other quinolones, levofloxacin should be used with great caution in patients with a predisposition to seizures. Such patients include patients with previous lesions of the central nervous system, such as stroke, severe traumatic brain injury; patients simultaneously taking drugs that lower the threshold for convulsive activity of the brain (for example, theophylline; fenbufen and other non-steroidal anti-inflammatory drugs (see section “Interaction with other drugs”). If seizures develop, treatment with levofloxacin should be discontinued.

Pseudomembranous colitis

Diarrhea that develops during or after treatment with levofloxacin, especially severe, persistent and/or bloody, may be a symptom of pseudomembranous colitis caused by Clostridium difficile. If pseudomembranous colitis is suspected, treatment with levofloxacin should be stopped immediately and specific antibiotic therapy (vancomycin, teicoplanin or oral metronidazole) should be started immediately. Drugs that inhibit intestinal motility are contraindicated.

Tendonitis and tendon rupture

Tendinitis, which rarely occurs with quinolone use, can sometimes lead to rupture of tendons, including the Achilles tendon, and can be bilateral. This adverse reaction may occur within 48 hours of starting treatment or several months after completion of fluoroquinolone therapy.

Elderly patients are more prone to developing tendinitis; In patients taking fluoroquinolones, the risk of tendon rupture may be increased with concomitant use of corticosteroids. In addition, post-transplant patients have an increased risk of developing tendonitis, so it is recommended to be careful when prescribing fluoroquinolones to this category of patients. In patients with impaired renal function, the daily dose should be adjusted based on QC.

Patients should be advised to remain calm at the first sign of tendonitis or tendon rupture and to contact their healthcare provider. If you suspect the development of tendonitis or tendon rupture, you should immediately stop treatment with the drug and begin appropriate treatment of the affected tendon, for example, by providing it with sufficient immobilization (see sections “Contraindications” and “Side effects”).

Hypersensitivity reactions

Levofloxacin can cause serious, potentially fatal hypersensitivity reactions (angioedema, anaphylactic shock) even with initial doses (see section “Side effects”). If they develop, patients should immediately stop taking the drug and consult a doctor.

Severe skin adverse reactions

Severe cutaneous adverse reactions have been reported with the use of levofloxacin, including toxic epidermal necrolysis (Lyell’s syndrome), Stevens-Johnson syndrome and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which can be life-threatening or fatal (see section “Side effects”). When prescribing the drug, patients should be informed of the signs and symptoms of severe cutaneous adverse reactions and be under close medical supervision. If signs and symptoms indicating the development of these adverse reactions occur, you should immediately stop taking Levofloxacin and consider alternative treatment. If a patient develops a severe adverse skin reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome, while using levofloxacin, the drug should not be restarted in that patient.

Disorders of the liver and biliary tract

Cases of liver necrosis, including fatal liver failure, have been reported with the use of levofloxacin, mainly in patients with severe underlying diseases, such as sepsis (see section “Side effects”). Patients should be warned to stop treatment and seek immediate medical attention if signs and symptoms of liver damage occur, such as anorexia, jaundice, dark urine, itching and abdominal pain.

Patients with impaired renal function

Since levofloxacin is excreted mainly through the kidneys, patients with impaired renal function require mandatory monitoring of renal function, as well as adjustment of the dosage regimen (see section “Dosage and Administration”). When treating elderly patients, it should be taken into account that patients in this group often have impaired renal function (see section “Dosage and Administration”).

Preventing the development of photosensitivity reactions

Although photosensitivity occurs very rarely with the use of levofloxacin, to prevent its development, patients are not recommended during treatment and during
48 hours after finishing treatment with levofloxacin, be exposed to strong sunlight or artificial ultraviolet irradiation (for example, visit a solarium).

Superinfection

As with the use of other antibiotics, the use of levofloxacin, especially for a long time, can lead to increased proliferation of resistant microorganisms (bacteria and fungi), which can cause changes in the normal human microflora. As a result, superinfection may develop. Therefore, during treatment, it is imperative to re-evaluate the patient’s condition, and, if superinfection develops during treatment, appropriate measures should be taken.

QT prolongation

Very rare cases of QT prolongation have been reported in patients taking fluoroquinolones, including levofloxacin.

When using fluoroquinolones, including levofloxacin, caution should be exercised in patients with known risk factors for prolongation of the QT interval: in patients with uncorrected electrolyte disturbances (with hypokalemia, hypomagnesemia); with congenital long QT syndrome; with heart disease (heart failure, myocardial infarction, bradycardia); with simultaneous use of drugs that can prolong the QT interval, such as class IA and III antiarrhythmic drugs, tricyclic antidepressants, macrolides, antipsychotics.

Elderly and female patients may be more sensitive to drugs that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used with caution (see sections “With caution”, “Dosage and administration”, “Side effects”, “Overdose” and “Interaction with other drugs”).

Patients with glucose-6-phosphate dehydrogenase deficiency

In patients with latent or manifest deficiency
glucose-6-phosphate dehydrogenase is predisposed to the development of hemolytic reactions during treatment with quinolones, which should be taken into account when treating with levofloxacin.

Dysglycemia (hypo- and hyperglycemia)

As with the use of other fluoroquinolones, cases of hyperglycemia and hypoglycemia have been observed with the use of levofloxacin. During therapy with levofloxacin, dysglycemia more often developed in elderly patients and patients with diabetes mellitus receiving concomitant therapy with oral hypoglycemic drugs (for example, glibenclamide) or insulin. When using levofloxacin in such patients, the risk of developing hypoglycemia, including hypoglycemic coma, increases. It is necessary to inform patients about the symptoms of hypoglycemia (confusion, dizziness, ravenous appetite, headache, nervousness, palpitations or increased heart rate, pale skin, perspiration, trembling, weakness). If the patient develops hypoglycemia, treatment with levofloxacin should be stopped immediately and appropriate therapy should be initiated. In these cases, it is recommended to switch to therapy with an antibiotic other than a fluoroquinolone, if possible. When treating levofloxacin in elderly patients and patients with diabetes mellitus, careful monitoring of blood glucose concentrations is recommended.

Peripheral neuropathy

Sensory and sensorimotor peripheral neuropathy, which may have a rapid onset, has been reported in patients taking fluoroquinolones, including levofloxacin. If the patient develops symptoms of neuropathy, levofloxacin should be discontinued. This minimizes the possible risk of developing irreversible changes. Patients should be informed to report any symptoms of neuropathy to their healthcare provider. Fluoroquinolones should not be prescribed to patients with a history of peripheral neuropathy.

Exacerbation of pseudoparalytic myasthenia gravis (myasthenia gravis)

Fluoroquinolones, including levofloxacin, are characterized by blocking
neuromuscular conduction activity and may increase muscle weakness in patients with myasthenia gravis. Post-marketing adverse reactions, including pulmonary failure requiring mechanical ventilation and death, have been associated with the use of fluoroquinolones in patients with myasthenia gravis. The use of levofloxacin in a patient with an established diagnosis of pseudoparalytic myasthenia gravis is not recommended (see section “Side Effects”).

Use for airborne anthrax infection

The use of levofloxacin in humans for this indication is based on susceptibility data from Bacillus anthracis obtained from in vitro and experimental animal studies, as well as limited data from the use of levofloxacin in humans. Treating physicians should refer to national and/or international documents that reflect the collectively developed point of view on the treatment of anthrax.

Psychotic reactions

Psychotic reactions, including suicidal ideation/attempts, have been reported in patients taking fluoroquinolones, including levofloxacin, sometimes after a single dose. In case of development of any side effects from the central nervous system, including mental disorders, treatment with levofloxacin should be stopped immediately and appropriate therapy should be prescribed. In these cases, it is recommended to switch to therapy with an antibiotic other than a fluoroquinolone, if possible. The drug should be prescribed with caution to patients with psychosis or patients with a history of mental illness (see section “With caution”).

Aortic aneurysm and dissection, heart valve regurgitation/regurgitation

Epidemiological studies have reported an increased risk of aortic aneurysm and aortic dissection, especially in elderly patients, as well as aortic and mitral valve regurgitation after the use of fluoroquinolones. In patients receiving fluoroquinolones, there have been cases of aortic aneurysm and dissection, sometimes complicated by rupture (including death), as well as regurgitation/insufficiency of any of the heart valves (see section “Side effects”).

Therefore, fluoroquinolones should be used only after careful benefit-risk assessment and consideration of other treatment options in patients with a family history of aortic aneurysm or congenital heart valve disease, or in patients with a known aortic aneurysm and/or aortic dissection or heart valve disease, or in the presence of other risk factors or conditions predisposing to the development of:

both aortic aneurysm and dissection, and heart valve regurgitation/insufficiency (eg, connective tissue diseases such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behçet’s disease, hypertension, rheumatoid arthritis);

or additionally:

aortic aneurysms and dissections (eg, vascular diseases such as Takayasu arteritis, giant cell arteritis, confirmed atherosclerosis, Sjögren’s syndrome);
regurgitation/insufficiency of the heart valve (eg, infective endocarditis).

The risk of developing aortic aneurysm and dissection, as well as their rupture, may be increased in patients concomitantly receiving systemic corticosteroids.

If patients experience sudden pain in the abdomen, chest, or back, they should contact their doctor immediately at the emergency room.

Patients should be advised to seek immediate medical attention if they experience acute shortness of breath, new palpitations, or swelling of the abdomen or lower extremities.

Visual impairment

If any visual impairment develops, immediate consultation with an ophthalmologist is necessary (see section “Side Effects”).

Acute pancreatitis

Patients taking levofloxacin may develop acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis. If nausea, malaise, abdominal discomfort and acute abdominal pain occur, the patient should immediately consult a doctor for a medical examination. If pancreatitis is suspected, levofloxacin should be discontinued and not restarted. The drug should be used with caution in patients with a history of pancreatitis (see section “With caution”).

Effect on laboratory tests

In patients taking levofloxacin, the determination of opiates in urine may lead to false-positive results, which should be confirmed by more specific methods.

Levofloxacin may inhibit the growth of Mycobacterium tuberculosis and subsequently lead to false-negative results of the bacteriological diagnosis of tuberculosis.

Impact on the ability to drive vehicles and machinery

Side effects of Levofloxacin, such as dizziness or vertigo, drowsiness and visual disturbances (see section “Side effects”), can reduce psychomotor reactions and the ability to concentrate. This may pose a risk in situations where these abilities are of particular importance (for example, when driving a car, when servicing machinery, when performing work in an unstable position).

Active ingredient

Levofloxacin

Composition

1 film-coated tablet, 250 mg contains:

Active ingredient: levofloxacin hemihydrate – 256.23 mg in terms of levofloxacin – 250.00 mg.

Excipients: microcrystalline cellulose (MCC-101) – 30.00 mg, sodium carboxymethyl starch – 17.50 mg, povidone-K25 – 15.00 mg, croscarmellose sodium – 8.27 mg, magnesium stearate – 5.00 mg, colloidal silicon dioxide – 3.00 mg.

Shell composition: polyvinyl alcohol – 7.035 mg, macrogol-4000 – 4.845 mg, titanium dioxide – 3.12 mg.

1 film-coated tablet, 500 mg, contains:

Active ingredient: levofloxacin hemihydrate – 512.46 mg in terms of levofloxacin – 500.00 mg.

Excipients: microcrystalline cellulose (MCC-101) – 60.00 mg, sodium carboxymethyl starch – 35.00 mg, povidone-K25 – 30.00 mg, croscarmellose sodium – 16.54 mg, magnesium stearate – 10.00 mg, colloidal silicon dioxide – 6.00 mg.

Shell composition: polyvinyl alcohol – 14.07 mg, macrogol-4000 – 9.69 mg, titanium dioxide – 6.24 mg.

Pregnancy

Levofloxacin is contraindicated for use in pregnant and breastfeeding women.

Contraindications

• hypersensitivity to levofloxacin or other quinolones, as well as to any of the excipients of the drug;
• epilepsy;
• pseudoparalytic myasthenia gravis (myasthenia gravis) (see sections “Side effects”, “Special instructions”);
• history of tendon damage when taking fluoroquinolones;
• childhood and adolescence up to 18 years of age (due to incomplete growth of the skeleton, since the risk of damage to the cartilaginous growth zones of bones cannot be completely excluded);
• pregnancy (the risk of damage to the cartilaginous growth zones of bones in the fetus cannot be completely excluded);
• the period of breastfeeding (the risk of damage to the cartilaginous growth zones of bones in a child cannot be completely eliminated).

With caution
• In patients predisposed to the development of seizures (in patients with previous lesions of the central nervous system (CNS); in patients simultaneously taking drugs that lower the threshold of convulsive activity of the brain, such as fenbufen, theophylline)
(see section “Interaction with other drugs”).
• In patients with latent or manifest deficiency
glucose-6-phosphate dehydrogenase (increased risk of hemolytic reactions during treatment with quinolones).
• In patients with impaired renal function (mandatory monitoring of renal function is required, as well as correction of the dosage regimen, see section “Dosage and Administration”).
• In patients with known risk factors for prolongation of the QT interval: in elderly patients; in female patients; in patients with uncorrected electrolyte disturbances (with hypokalemia, hypomagnesemia); with congenital long QT syndrome; with heart disease (heart failure, myocardial infarction, bradycardia); while taking medications that can prolong the QT interval (antiarrhythmic drugs of class IA and III, tricyclic antidepressants, macrolides, antipsychotics) (see sections “Overdose”, “Interaction with other drugs”, “Special instructions”).
• In patients with diabetes mellitus receiving oral hypoglycemic drugs (eg, glibenclamide) or insulin drugs (increased risk of hypoglycemia).
• In patients with severe adverse reactions to other fluoroquinolones, such as severe neurological reactions (increased risk of developing similar adverse reactions with levofloxacin).
• In patients with psychosis or in patients with a history of mental illness (see section “Special instructions”).
• In elderly patients, in patients after transplantation, as well as with concomitant use of glucocorticosteroids (increased risk of tendinitis and tendon rupture) (see section “Special instructions”).
• In patients with porphyria (risk of exacerbation of porphyria, see section “Side effects”).
• In patients with a history of pancreatitis (see subsection “Special instructions”).
• In patients with an aortic aneurysm, with a family history of congenital heart valve disease, or in patients with a known aortic aneurysm and/or aortic dissection, with heart valve disease, or with other risk factors or conditions that predispose to the development of an aortic aneurysm or aortic dissection, or regurgitation/insufficiency of the heart valve (eg, Marfan syndrome, Ehlers-Danlos syndrome, Turner syndrome, Behçet’s disease, arterial hypertension, rheumatoid arthritis, vascular diseases such as Takayasu’s arteritis, giant cell arteritis, confirmed atherosclerosis, Sjögren’s syndrome, infective endocarditis) (see section “Special Instructions”).

Side Effects

The side effects listed below are presented in accordance with the following gradations of frequency of their occurrence: very often (≥ 1/10); often (≥ 1/100, but < 1/10); uncommon (≥ 1/1000, but < 1/100); rare (≥ 1/10000, but < 1/1000); very rare (< 1/10000); frequency unknown (cannot be estimated from available data).

Data obtained from clinical studies and post-registration use of levofloxacin.

Infections and infestations

Uncommon: fungal infections, development of resistance of pathogenic microorganisms.

Blood and lymphatic system disorders

Uncommon: leukopenia (decreased number of leukocytes in peripheral blood), eosinophilia (increased number of eosinophils in peripheral blood);

Rarely: neutropenia (decreased number of neutrophils in peripheral blood), thrombocytopenia (decreased number of platelets in peripheral blood);

Frequency unknown (post-registration data): pancytopenia (decrease in the number of all formed elements in the peripheral blood), agranulocytosis (absence or sharp decrease in the number of granulocytes in the peripheral blood), hemolytic anemia.

Immune system disorders

Rarely: angioedema;

Frequency unknown (post-marketing data): anaphylactic shock, anaphylactoid shock.

Anaphylactic and anaphylactoid reactions can sometimes develop even after taking the first dose of the drug.

Metabolic and nutritional disorders

Uncommon: anorexia;

Rarely: hypoglycemia, especially in patients with diabetes mellitus (possible signs of hypoglycemia: voracious appetite, nervousness, perspiration, trembling);

Frequency unknown: hyperglycemia, severe hypoglycemia, up to the development of hypoglycemic coma (especially in elderly patients, in patients with diabetes mellitus, taking oral hypoglycemic agents or receiving insulin treatment (see section “Special Instructions”).

Mental disorders*

Often: insomnia;

Uncommon: feeling of restlessness, anxiety, confusion;

Rarely: mental disorders (for example, hallucinations, paranoia), depression, agitation (excitement), sleep disturbances, nightmares;

Frequency unknown (post-registration data): mental disorders with behavioral disorders with self-harm, including suicidal thoughts and suicide attempts, nervousness, memory impairment, delirium (including attention problems, disorientation).

Nervous system disorders*

Common: headache, dizziness;

Uncommon: drowsiness, tremor, dysgeusia (taste perversion);

Rarely: paresthesia, convulsions (see section “Special instructions”);

Frequency unknown (post-marketing data): peripheral sensory neuropathy, peripheral sensorimotor neuropathy (see section “Special Instructions”), dyskinesia, extrapyramidal disorders, ageusia (loss of taste), parosmia (disorder of the sense of smell, especially the subjective sensation of an objectively absent smell), including loss of smell; fainting, increased intracranial pressure (benign intracranial hypertension, pseudotumor cerebri).

Visual disorders*

Rarely: visual disturbances such as blurred vision;

Frequency unknown (post-marketing data): transient vision loss, uveitis.

Disorders of the hearing organ and labyrinth*

Uncommon: vertigo (a feeling of deviation or spinning of one’s own body or surrounding objects);

Rarely: ringing in the ears;

Frequency unknown (post-marketing data): hearing loss, hearing loss.

Cardiac disorders**

Rarely: sinus tachycardia, palpitations;

Frequency unknown (post-registration data): prolongation of the QT interval, ventricular arrhythmias, ventricular tachycardia, ventricular tachycardia of the “pirouette” type, which can lead to cardiac arrest (see sections “Overdose”, “Special instructions”).

Vascular disorders**

Rarely: decreased blood pressure.

Respiratory, thoracic and mediastinal disorders

Uncommon: shortness of breath;

Frequency unknown (post-registration data): bronchospasm, allergic pneumonitis.

Gastrointestinal disorders

Common: diarrhea, vomiting, nausea;

Uncommon: abdominal pain, dyspepsia, flatulence, constipation;

Frequency unknown (post-registration data): hemorrhagic diarrhea, which in very rare cases may be a sign of enterocolitis, including pseudomembranous colitis (see section “Special instructions”), pancreatitis.

Disorders of the liver and biliary tract

Often: increased activity of liver enzymes in the blood (for example, alanine aminotransferase (ALT), aspartate aminotransferase (AST)), increased activity of alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT);

Uncommon: increased concentration of bilirubin in the blood;

Frequency unknown (post-marketing data): severe liver failure, including cases of acute liver failure, sometimes fatal, especially in patients with severe underlying disease (for example, in patients with sepsis) (see section “Special Instructions”); hepatitis, jaundice.

Skin and subcutaneous tissue disorders

Uncommon: rash, itching, urticaria, hyperhidrosis;

Rarely: fixed drug rash, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section “Special instructions”);

Frequency unknown (post-registration data): toxic epidermal necrolysis, Stevens-Johnson syndrome, exudative erythema multiforme, photosensitivity reactions (increased sensitivity to solar and ultraviolet radiation) (see section “Special instructions”), leukocytoclastic vasculitis, stomatitis.

Reactions from the skin and mucous membranes may sometimes occur after taking the first dose of the drug.

Muscle, skeletal and connective tissue disorders*

Uncommon: arthralgia, myalgia;

Rarely: tendon damage, including tendonitis (for example, Achilles tendon), muscle weakness, which can be especially dangerous in patients with myasthenia gravis (see section “Special instructions”);

Not known (post-marketing data): rhabdomyolysis, tendon rupture (eg, Achilles tendon. This side effect may occur for
48 hours after the start of treatment and can be bilateral (see also section “Special Instructions”)), ligament rupture, muscle rupture, arthritis.

Renal and urinary tract disorders

Uncommon: increased serum creatinine concentration;

Rarely: acute renal failure (for example, due to the development of interstitial nephritis).

General disorders and reactions at the injection site*

Uncommon: asthenia;

Rarely: pyrexia (fever);

Not known: pain (including pain in the back, chest and limbs).

Other possible adverse effects that apply to all fluoroquinolones

Very rare: attacks of porphyria (a very rare metabolic disease) in patients with porphyria.

*In very rare cases with the use of quinolones and fluoroquinolones, sometimes regardless of the underlying risk factors, long-lasting (up to several months or years), disabling and potentially irreversible serious adverse reactions to the drug have been reported, affecting several, and sometimes multiple, classes of organ systems and sensory organs (including reactions such as tendonitis, tendon rupture, arthralgia, pain in the extremities, gait disturbance, neuropathies associated with paresthesia, depression, increased fatigue, memory impairment, sleep disturbances, as well as hearing, vision, taste and smell disorders) (see section “Special Instructions”).

**In patients receiving fluoroquinolones, cases of aortic aneurysm and dissection, sometimes complicated by rupture (including death), as well as regurgitation/incompetence of any heart valve have been reported (see section “Special Instructions”).

Interaction

Interactions requiring caution

With preparations containing magnesium, aluminum, iron and zinc, didanosine

Drugs containing divalent or trivalent cations, such as zinc or iron salts (medicines for the treatment of anemia), magnesium- and/or aluminum-containing drugs (such as antacids), didanosine (only dosage forms containing aluminum or magnesium as a buffer) are recommended to be taken at least 2 hours before or 2 hours after taking levofloxacin.

Calcium salts have a minimal effect on the absorption of levofloxacin when taken orally.

With sucralfate

The effect of levofloxacin is significantly weakened by the simultaneous use of sucralfate (a drug for protecting the gastric mucosa).

For patients receiving levofloxacin and sucralfate, it is recommended that sucralfate be taken 2 hours after taking levofloxacin.

With theophylline, fenbufen or other drugs from the group of non-steroidal anti-inflammatory drugs that reduce the threshold of convulsive readiness of the brain

No pharmacokinetic interaction of levofloxacin with theophylline was detected.

However, with the simultaneous use of quinolones and theophylline, non-steroidal anti-inflammatory drugs and other drugs that reduce the threshold of convulsive readiness of the brain, a pronounced decrease in the threshold of convulsive readiness of the brain is possible.

The concentration of levofloxacin while taking fenbufen increases only by 13%.

With indirect anticoagulants (vitamin K antagonists)

In patients treated with levofloxacin in combination with indirect anticoagulants (for example, warfarin), an increase in prothrombin time/international normalized ratio and/or the development of bleeding, including severe bleeding, was observed. Therefore, with the simultaneous use of indirect anticoagulants and levofloxacin, regular monitoring of blood coagulation parameters is necessary.

With probenecid and cimetidine

When simultaneous use of drugs that interfere with renal tubular secretion, such as probenecid and cimetidine, and levofloxacin, caution should be exercised, especially in patients with renal failure.

The elimination (renal clearance) of levofloxacin is slowed down by cimetidine by 24% and probenecid by 34%. This is unlikely to be of clinical significance if renal function is normal.

With cyclosporine

Levofloxacin increased T1/2 of cyclosporine by 33%. Since this increase is clinically insignificant, no dose adjustment of cyclosporine is required when used concomitantly with levofloxacin.

With glucocorticosteroids

Concomitant use of glucocorticosteroids increases the risk of tendon rupture.

With drugs that prolong the QT interval

Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs that prolong the QT interval (for example, class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics).

Others

Clinical and pharmacological studies conducted to study the possible pharmacokinetic interactions of levofloxacin with digoxin, glibenclamide, ranitidine and warfarin showed that the pharmacokinetics of levofloxacin when used simultaneously with these drugs does not change sufficiently to be of clinical significance.

Overdose

Symptoms
Based on data obtained from toxicological studies in animals, the most important expected symptoms of acute levofloxacin overdose are central nervous system symptoms (impaired consciousness, including confusion, dizziness and convulsions).
During post-marketing use in overdose, central nervous system effects have been observed, including confusion, convulsions, hallucinations, and tremors.
Possible development of nausea and erosion of the mucous membrane of the gastrointestinal tract.
In clinical pharmacological studies conducted with doses of levofloxacin exceeding therapeutic doses, prolongation of the QT interval was observed.
Treatment
In case of overdose, careful monitoring of the patient is required, including electrocardiogram monitoring. Treatment is symptomatic. In case of acute overdose of levofloxacin tablets, gastric lavage and administration of antacids are indicated to protect the gastric mucosa. Levofloxacin is not eliminated by dialysis (hemodialysis, peritoneal dialysis and continuous ambulatory peritoneal dialysis). There is no specific antidote.

Storage conditions

At a temperature not exceeding 25 °C.
Keep out of the reach of children.

Shelf life

3 years. Do not use after expiration date.

Manufacturer

Ozon, Russia