INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOFLOXACIN-NOVOFARM (levofloxacin-NOVOFARM)

Composition:

active substance: levofloxacin hemihydrate;

1 ml of solution contains levofloxacin hemihydrate equivalent to 5 mg of levofloxacin;

excipients: sodium chloride, sodium hydroxide, hydrochloric acid concentrated, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical characteristics: clear greenish-yellow solution. Theoretical osmolarity — 302 mOsmol/L.

Pharmacotherapeutic group. Antibacterial agents of the quinolone group. Fluoroquinolones.

ATC code J01MA12.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone group, the S(–)-enantiomer of the racemic mixture of the drug ofloxacin.

Mechanism of action

Levofloxacin, as an antibacterial agent of the fluoroquinolone group, acts on the DNA-DNA gyrase complex and topoisomerase IV.

Pharmacokinetic/pharmacodynamic relationship

The degree of antibacterial activity of levofloxacin depends on the ratio of the maximum serum concentration (Cmax) or the area under the pharmacokinetic curve (AUC) to the minimum inhibitory concentration (MIC).

Mechanism of resistance

Resistance to levofloxacin develops through stepwise mutations in the target site of both types of topoisomerase II, DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as permeability (characteristic of Pseudomonas aeruginosa) and efflux mechanisms, may also affect susceptibility to levofloxacin.

The primary mechanism of resistance results from mutations in the gyr-A genes. In vitro, cross-resistance exists between levofloxacin and other fluoroquinolones. Due to its mechanism of action, cross-resistance between levofloxacin and other classes of antibacterial agents is usually not observed.

Clinical breakpoints

The recommended breakpoints for levofloxacin MIC values established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which distinguish susceptible microorganisms from those with intermediate susceptibility (moderately resistant), and intermediate from resistant organisms, are presented in Table 1 for MIC testing (mg/L).

Table 1

Clinical breakpoints for levofloxacin (version 10.0, 2020-01-01)

Pathogen	Susceptible	Resistant
Enterobacteriaceae	≤ 0.5 mg/L	> 1 mg/L
Pseudomonas spp.	≤ 0.001 mg/L	> 1 mg/L
Acinetobacter spp.	≤ 0.5 mg/L	> 1 mg/L
Staphylococcus spp. Coagulase-negative staphylococci	≤ 0.001 mg/L	> 1 mg/L
Enterococcus spp.1	≤ 4 mg/L	> 4 mg/L
Streptococcus pneumoniae	≤ 0.001 mg/L	> 2 mg/L
Streptococcus A, B, C, G	≤ 0.001 mg/L	> 2 mg/L
Haemophilus influenzae	≤ 0.06 mg/L	> 0.06 mg/L
Moraxella catarrhalis	≤ 0.125 mg/L	> 0.125 mg/L
Helicobacter pylori	≤ 1 mg/L	> 1 mg/L
Aerococcus sanguinicola and urinae2	≤ 2 mg/L	> 2 mg/L
Aeromonas spp.	≤ 0.5 mg/L	> 1 mg/L
Pharmacokinetic-pharmacodynamic breakpoints (non-species related)	≤ 0.5 mg/L	> 1 mg/L

1 Only uncomplicated urinary tract infections.

2 Susceptibility depends on sensitivity to ciprofloxacin.

The prevalence of resistance in individual species may vary geographically and over time — it is advisable to obtain local information on resistance, especially when treating severe infections. Advice from a specialist should be sought if local resistance prevalence renders the usefulness of the agent at least questionable for certain types of infections.

Typically susceptible species

Aerobic Gram-positive bacteria

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

Aerobic Gram-negative bacteria

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

Anaerobic bacteria

Peptostreptococcus.

Others

Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamydia trachomatis, Legionella pneumophila, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum.

Species with potential for acquired resistance

Aerobic Gram-positive bacteria

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

Aerobic Gram-negative bacteria

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

Anaerobic bacteria

Bacteroides fragilis.

Naturally resistant strains

Aerobic Gram-positive bacteria

Enterococcus faecium

* Methicillin-resistant Staphylococcus aureus is likely to exhibit co-resistance to fluoroquinolones, including levofloxacin.

Pharmacokinetics.

Absorption

Levofloxacin is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations (Cmax) reached within 1–2 hours. Absolute bioavailability is approximately 99–100%.

Food has almost no effect on the absorption of levofloxacin.

Steady-state concentrations are achieved within 48 hours with dosing regimens of 500 mg once or twice daily.

Distribution

Approximately 30–40% of levofloxacin is protein-bound in plasma. The mean volume of distribution of levofloxacin is about 100 L after single and repeated 500 mg doses, indicating extensive tissue distribution throughout the body.

Penetration into tissues and body fluids

Levofloxacin penetrates well into bronchial mucosa, epithelial lining fluid, alveolar macrophages, lung tissue, skin (vesicle content), prostate tissue, and urine. However, levofloxacin penetrates poorly into cerebrospinal fluid.

Biotransformation

Levofloxacin undergoes minimal metabolism. Metabolites include desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the administered dose excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.

Elimination

After both oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life of 6–8 hours). Elimination occurs primarily via the kidneys (over 85% of the administered dose). The mean total systemic clearance of levofloxacin after a single 500 mg dose was

175 ± 29.2 mL/min. There is no significant difference in the pharmacokinetics of levofloxacin after oral and intravenous administration, indicating interchangeability of these routes.

Linearity

Levofloxacin exhibits linear pharmacokinetics over the dose range of 50 to 1000 mg.

Patients with renal impairment

Renal impairment affects the pharmacokinetics of levofloxacin. With reduced renal function, renal elimination and clearance decrease, and elimination half-life increases, as shown in Table 2 below.

Table 2

Creatinine clearance (ml/min)	< 20	20–40	50–80
Renal clearance (ml/min)	13	26	57
Elimination half-life (hours)	35	27	9

Geriatric Patients

There are no significant differences in the pharmacokinetics of levofloxacin between younger and elderly patients, except for differences related to creatinine clearance.

Gender Differences

Separate analysis of male and female patients demonstrated minor differences in the pharmacokinetics of levofloxacin depending on gender. There is no evidence that these gender-related differences are clinically significant.

Preclinical Safety Data

Preclinical data reveal no special hazard to humans based on studies of single-dose toxicity, repeated-dose toxicity, carcinogenicity, reproductive toxicity, and developmental toxicity.

Levofloxacin did not impair fertility or reproductive function in rats. The only manifestation of maternal reproductive toxicity was delayed fetal development.

Levofloxacin did not induce gene mutations in bacteria or mammalian cells, although chromosomal aberrations were observed in vitro in Chinese hamster lung cells. These effects are associated with inhibition of topoisomerase II. In vivo tests (micronucleus, sister chromatid exchange, unscheduled DNA synthesis, dominant lethal tests) showed no genotoxic potential.

Levofloxacin showed phototoxic activity only at very high doses in mouse studies. Levofloxacin showed no genotoxic potential in the photomutagenicity assay and reduced tumor development in the photocarcinogenicity study.

Like other fluoroquinolones, levofloxacin demonstrated effects on cartilage (formation of vesicles and cavities) in rats and dogs. These effects were more pronounced in young animals.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to levofloxacin:

Community-acquired pneumonia;
Complicated skin and soft tissue infections (for the aforementioned infections, the medicinal product should be used only when the use of other antibacterial agents, which are usually recommended for initial treatment of these infections, is inappropriate or impossible);
Complicated urinary tract infections (including pyelonephritis);
Chronic bacterial prostatitis;
Pulmonary form of anthrax: post-exposure prophylaxis and treatment.

Official recommendations on appropriate use of antibacterial agents should be taken into account.

Contraindications.

Hypersensitivity to levofloxacin, other fluoroquinolones, or to any of the excipients of the medicinal product;
Epilepsy;
Tendon damage associated with the use of fluoroquinolones;
Pediatric age (under 18 years);
Pregnancy and breastfeeding.

Special precautions.

The medicinal product should be used immediately (within 3 hours) after perforation of the rubber stopper to prevent bacterial contamination. Protection from light during infusion is not required. The medicinal product is intended for single use only. Do not use any remaining medicinal product.

The solution should be inspected visually before use. Only clear greenish-yellow solution free from particles should be used.

As with all other medicinal products, unused solution should be disposed of according to local regulations.

Mixing with other infusion solutions:

Levofloxacin is compatible with the following infusion solutions:

0.9% sodium chloride solution;
5% glucose injection solution;
2.5% glucose in Ringer's solution;
combined parenteral nutrition solutions (amino acids, glucose, electrolytes).

For incompatibilities, see section "Incompatibilities".

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on levofloxacin

Theophylline, fenbufen, or similar non-steroidal anti-inflammatory medicinal products

No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant reduction in seizure threshold may occur with concomitant administration of quinolones and theophylline, non-steroidal anti-inflammatory drugs, and other agents that reduce seizure threshold. The concentration of levofloxacin in the presence of fenbufen was approximately 13% higher than with levofloxacin alone.

Probenecid and cimetidine

Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin. Renal clearance of levofloxacin decreases by 24% in the presence of cimetidine and by 34% with probenecid, as both medicinal products are capable of blocking tubular secretion of levofloxacin. However, at the doses tested in the study, it is unlikely that statistically significant kinetic differences would have clinical significance. Levofloxacin should be used with caution concomitantly with medicinal products affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other information

The following medicinal products do not exert any clinically significant effect on the pharmacokinetics of levofloxacin when administered concomitantly: calcium carbonate, digoxin, glyburide, ranitidine.

Effect of levofloxacin on other medicinal products

Cyclosporine

The elimination half-life of cyclosporine increases by 33% when administered concomitantly with levofloxacin.

Vitamin K antagonists

When used concomitantly with vitamin K antagonists (e.g., warfarin), increased results in coagulation tests (prothrombin time/international normalized ratio) and/or bleeding, which may be severe, have been observed. Therefore, coagulation parameters should be monitored in patients receiving concomitant vitamin K antagonists (see section "Special precautions. QT interval prolongation").

Medicinal products that prolong the QT interval

Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, and antipsychotic medicinal products) (see section "Special precautions. QT interval prolongation").

Other significant information

No effect of levofloxacin on the pharmacokinetics of theophylline (a substrate of CYP1A2 enzyme) has been observed, indicating that levofloxacin is not an inhibitor of CYP1A2.

Special precautions for use.

The use of the medicinal product should be avoided in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones. Treatment of these patients with levofloxacin should be initiated only if there are no alternative treatment options and after careful assessment of benefit/risk ratio.

Methicillin-resistant S. aureus

There is a very high likelihood of cross-resistance to fluoroquinolones, including levofloxacin, in methicillin-resistant S. aureus (MRSA). Therefore, levofloxacin is not recommended for the treatment of infections known or suspected to be caused by MRSA, except in cases where laboratory testing has confirmed susceptibility of the pathogen to levofloxacin.

Resistance to fluoroquinolones in E. coli (the most common causative agent of urinary tract infections) varies across countries. Local prevalence of fluoroquinolone resistance in E. coli should be taken into account when prescribing fluoroquinolones.

Pulmonary anthrax: the use of the drug for treatment in humans is based on in vitro data showing susceptibility of Bacillus anthracis, experimental animal data, and limited human experience. Physicians should refer to national and/or international established treatment guidelines for anthrax.

Long-term, disabling and potentially irreversible serious adverse reactions

Very rarely, in patients receiving quinolones and fluoroquinolones, regardless of age or presence of risk factors, long-term (lasting several months or years), disabling and potentially irreversible serious adverse reactions affecting various body systems (musculoskeletal, nervous, psychiatric, and sensory organs) have been observed. The medicinal product should be discontinued immediately at the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.

Duration of infusion

The recommended duration of infusion is at least 30 minutes for 250 mg or 60 minutes for 500 mg of levofloxacin infusion solution. Tachycardia and transient decrease in blood pressure have been reported during ofloxacin infusion. In rare cases, sudden drop in blood pressure and circulatory collapse may occur. If a significant drop in blood pressure occurs during levofloxacin (L-isomer of ofloxacin) infusion, administration of the drug should be stopped immediately.

Tendinitis and tendon rupture

Tendinitis and tendon ruptures (particularly of the Achilles tendon), sometimes bilateral, may occur within 48 hours of initiating treatment with quinolones and fluoroquinolones. Cases of these complications have been reported even several months after discontinuation of treatment in patients who received daily doses of 1000 mg levofloxacin. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with impaired renal function, transplant recipients, and patients receiving concomitant corticosteroids. Therefore, concomitant use of the drug with corticosteroids should be avoided.

At the first signs of tendinitis (e.g., painful swelling, inflammation), levofloxacin should be discontinued and alternative therapy considered. The affected limb should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy develop.

Myoclonus

Cases of myoclonus have been reported in patients receiving levofloxacin (see section "Adverse reactions"). The risk of myoclonus is increased in elderly patients and in patients with renal impairment if the dose of levofloxacin is not adjusted according to creatinine clearance. Levofloxacin should be discontinued immediately upon the first occurrence of myoclonus, and appropriate treatment initiated.

Clostridium difficile-associated disease

Diarrhea, especially severe, persistent and/or bloody diarrhea, occurring during or after treatment with levofloxacin (including several weeks after treatment) may be a symptom of Clostridium difficile-associated disease. The most severe form of this condition is pseudomembranous colitis (see section "Adverse reactions"). Therefore, physicians should consider the possibility of Clostridium difficile-associated disease in patients who develop severe diarrhea during or after treatment with levofloxacin. If Clostridium difficile-associated disease is suspected, levofloxacin should be discontinued immediately and appropriate treatment initiated without delay. Medicinal products that inhibit intestinal motility are contraindicated in this case.

Patients with predisposition to seizures

Quinolones may lower the seizure threshold and provoke seizures. Levofloxacin is contraindicated in patients with a history of epilepsy (see section "Contraindications"). As with other quinolones, the drug should be used with extreme caution in patients predisposed to seizures and when used concomitantly with substances that lower the seizure threshold, such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If seizures occur (see section "Adverse reactions"), treatment with levofloxacin should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or manifest deficiency of glucose-6-phosphate dehydrogenase activity are prone to hemolytic reactions when treated with quinolone antibacterial agents; therefore, levofloxacin should be used with caution in such patients due to the possibility of hemolysis.

Patients with renal impairment

Since levofloxacin is primarily eliminated via the kidneys, dose adjustment is required in patients with impaired renal function (renal insufficiency) (see section "Method of administration and dosage").

Hypersensitivity reactions

Levofloxacin may cause serious, potentially fatal hypersensitivity reactions (e.g., angioedema, anaphylactic shock), in some cases even after the first dose of the drug. If hypersensitivity reactions occur, levofloxacin should be discontinued, medical advice sought, and appropriate treatment initiated.

Severe bullous reactions

Severe skin reactions, including toxic epidermal necrolysis (also known as Lyell's syndrome), Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with levofloxacin use, which may be life-threatening (see section "Adverse reactions"). Patients should be informed about the signs and symptoms of severe skin reactions when levofloxacin is prescribed. If symptoms suggestive of such reactions occur, levofloxacin should be discontinued immediately and alternative therapy considered. If a patient develops severe skin adverse reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, or drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) during treatment with levofloxacin, re-administration of levofloxacin is absolutely contraindicated.

Alteration in blood glucose levels

As with other quinolones and fluoroquinolones, changes in blood glucose levels have been reported during levofloxacin use, including both hypoglycemia and hyperglycemia, usually observed in patients with diabetes mellitus who were concurrently taking oral hypoglycemic agents (e.g., glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. Close monitoring of blood glucose levels is recommended in diabetic patients (see section "Adverse reactions"). Levofloxacin treatment should be discontinued immediately if disturbances in blood glucose levels are reported, and alternative non-fluoroquinolone antibacterial therapy should be considered.

Prevention of photosensitization

Cases of photosensitization have been reported during levofloxacin use (see section "Adverse reactions"). To prevent photosensitization, patients are advised to avoid exposure to strong sunlight or artificial sources of UV radiation (e.g., UV lamps, sunbeds) during treatment and for 48 hours after discontinuation of levofloxacin.

Patients receiving vitamin K antagonists

Due to the possible increase in coagulation parameters (prothrombin time/international normalized ratio) and/or increased frequency of hemorrhagic complications in patients receiving levofloxacin in combination with a vitamin K antagonist (e.g., warfarin), coagulation parameters should be monitored when these agents are used concomitantly (see section "Interaction with other medicinal products and other forms of interaction").

Psychotic reactions

Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. Very rarely, these progressed to suicidal thoughts and self-destructive behavior, sometimes after only a single dose of levofloxacin (see section "Adverse reactions"). If such reactions occur, levofloxacin should be discontinued and appropriate measures taken. Levofloxacin should be used with caution in patients with psychotic disorders or a history of psychiatric illness.

QT interval prolongation

Fluoroquinolones, including levofloxacin, should be used with caution in patients with known risk factors for QT interval prolongation, such as:

congenital or acquired QT prolongation syndrome;
concomitant use of medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics);
electrolyte imbalance (e.g., hypokalemia, hypomagnesemia);
cardiac disease (e.g., heart failure, myocardial infarction, bradycardia) (see sections "Method of administration and dosage. Dosage in elderly patients", "Interaction with other medicinal products and other forms of interaction", "Adverse reactions", "Overdose").

Elderly patients and women may be more sensitive to drugs that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used with caution in these patient groups.

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. If symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur, patients should inform their physician promptly to prevent progression to potentially irreversible conditions.

Hepatobiliary disorders

Cases of liver necrosis up to hepatic failure with fatal outcome have been reported with levofloxacin use (mostly in patients with severe underlying conditions such as sepsis) (see section "Adverse reactions"). Patients should be advised to discontinue treatment and seek medical advice if symptoms of liver disease occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.

Exacerbation of myasthenia gravis

Fluoroquinolones, including levofloxacin, have neuromuscular blocking effects and may exacerbate muscle weakness in patients with myasthenia gravis. In the post-marketing period, serious adverse reactions including fatal outcomes and conditions requiring respiratory support have been associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances

If any visual disturbances or ocular adverse reactions occur during levofloxacin intake, immediate consultation with an ophthalmologist is required (see sections "Adverse reactions" and "Ability to influence reaction speed when driving or operating machinery").

Superinfection

The use of levofloxacin, especially prolonged use, may lead to overgrowth of microorganisms resistant to the drug. If superinfection develops during therapy, appropriate measures should be taken.

Effect on laboratory test results

In patients receiving levofloxacin, urine opiate screening may yield false-positive results. Confirmation of positive opiate screening results by more specific methods may be necessary.

Levofloxacin may inhibit the growth of Mycobacterium tuberculosis, thereby causing false-negative results in bacteriological diagnosis of tuberculosis.

Aneurysm, aortic dissection and cardiac valve regurgitation/insufficiency

Epidemiological data suggest an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and aortic and mitral valve regurgitation following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any cardiac valve have been reported in patients receiving fluoroquinolones (see section "Adverse reactions").

Therefore, fluoroquinolones should be used only after careful benefit/risk assessment and consideration of alternative therapeutic options in patients with a family history of aneurysm or congenital heart valve defects, or those diagnosed with aneurysm and/or aortic dissection, or with heart valve disease, or in the presence of other risk factors, namely:

risk factors for both aortic aneurysm/dissection and cardiac valve regurgitation/insufficiency: connective tissue disorders such as Marfan syndrome, Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, hypertension, rheumatoid arthritis;
risk factors for aortic aneurysm and dissection: vascular disorders such as Takayasu arteritis or giant cell arteritis, atherosclerosis, Sjögren's syndrome;
risk factors for cardiac valve regurgitation/insufficiency: infective endocarditis.

The risk of aortic aneurysm, dissection, and rupture is increased in patients receiving systemic corticosteroids concomitantly.

Patients should seek immediate medical attention in case of sudden abdominal, chest, or back pain.

Patients should be advised to seek immediate medical help if acute dyspnea, new-onset palpitations, or development of abdominal or lower limb edema occurs.

Acute pancreatitis

Acute pancreatitis may occur in patients taking levofloxacin. Patients should be informed about the typical symptoms of acute pancreatitis. Patients experiencing nausea, malaise, abdominal discomfort, severe abdominal pain, or vomiting should undergo immediate medical evaluation. Levofloxacin should be discontinued if acute pancreatitis is suspected. Re-administration of levofloxacin is not recommended if acute pancreatitis is confirmed. Caution should be exercised when using levofloxacin in patients with a history of pancreatitis (see section "Adverse reactions").

Blood disorders

During treatment with levofloxacin, bone marrow suppression may develop, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, or agranulocytosis (see section "Adverse reactions"). If such disorders are suspected, blood parameters should be monitored and discontinuation of levofloxacin therapy considered in case of abnormalities.

Special warnings regarding excipients

The medicinal product contains 15.8 mmol (363 mg) of sodium per 100 ml of solution, which should be taken into account if the patient is on a controlled-salt diet.

Use during pregnancy or breastfeeding

The medicinal product is contraindicated during pregnancy or breastfeeding.

Data on the use of levofloxacin in pregnant and breastfeeding women are limited. Animal studies do not indicate direct or indirect harmful effects on reproductive function. Due to the lack of human studies (and animal experiments indicating a risk of cartilage damage in weight-bearing joints of growing animals by fluoroquinolones), levofloxacin should not be administered to pregnant women or women who are breastfeeding. If pregnancy is diagnosed during treatment, the physician should be informed. Breastfeeding must be discontinued if treatment with the medicinal product is necessary.

Levofloxacin did not cause impairment of fertility or reproductive function in animals.

Ability to influence reaction speed when driving or operating machinery

Some adverse reactions (e.g., dizziness/vertigo, somnolence, visual disturbances) may impair a patient's ability to concentrate and reaction speed, thereby increasing the risk in situations where these abilities are critical (e.g., driving a vehicle or operating machinery).

Dosage and Administration

The medicinal product is administered intravenously slowly, once or twice daily. The dosage depends on the type and severity of infection, as well as on the susceptibility of the likely pathogen to the medicinal product. Treatment with levofloxacin, after initial intravenous administration, may be completed with the oral formulation, provided such treatment is appropriate for the individual patient. Due to the bioequivalence of parenteral and oral dosage forms, the same dose may be used.

Table 3

Dosage for patients with normal renal function,

in whom creatinine clearance is over 50 mL/min

Indications	Dose, mg	Number of daily doses	Treatment duration1
Community-acquired pneumonia	500	1–2 times	7–14 days
Pyelonephritis	500	1 time	7–10 days
Complicated urinary tract infections	500	1 time	7–14 days
Chronic bacterial prostatitis	500	1 time	28 days
Complicated skin and soft tissue infections	500	1–2 times	7–14 days
Pulmonary form of anthrax	500	1 time	8 weeks

1Depending on the patient's condition, a switch from initial intravenous administration to oral administration at the same dosage may be possible after a few days.

Table 4

Dosage for patients with impaired renal function
in whom creatinine clearance is less than 50 ml/min

Creatinine clearance, mL/min

Dosing regimen

(depending on severity of infection and nosological form)

250 mg / 24 h

500 mg / 24 h

500 mg / 12 h

50–20

initial dose — 250 mg, subsequent —

125 mg / 24 h