Levinor

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVINOR (LEVINOR)

Composition:

Active substance: levofloxacin;

100 ml of solution contain levofloxacin hemihydrate equivalent to 500 mg of anhydrous 100% levofloxacin;

Excipients: sodium chloride, disodium edetate, hydrochloric acid diluted, sodium hydroxide, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear yellow to yellowish-green liquid. Theoretical osmolarity — 300 mOsmol/L.

Pharmacotherapeutic group. Antibacterials for systemic use. Fluoroquinolones. Levofloxacin. ATC code J01MA12.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class and the S-enantiomer of the racemic mixture of the drug ofloxacin.

Mechanism of action

As a fluoroquinolone-class antibacterial agent, levofloxacin acts on the DNA-DNA gyrase complex and topoisomerase IV.

Pharmacokinetic (PK)/pharmacodynamic (PD) relationship

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

Mechanism of resistance

Resistance to levofloxacin develops gradually due to mutations in the target genes of type II topoisomerases, DNA gyrase, and topoisomerase IV. Other resistance mechanisms, such as reduced permeability of the bacterial envelope (typical for Pseudomonas aeruginosa) and efflux mechanisms, may also affect susceptibility to levofloxacin. 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 generally not observed.

Breakpoints

The recommended breakpoints for MIC of levofloxacin established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which distinguish susceptible microorganisms from moderately susceptible organisms, and moderately susceptible from resistant organisms, are presented in the table below.

EUCAST clinical MIC 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 aureus 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
Group A, B, C and G streptococci	≤ 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
PK-PD (non-species specific) breakpoints	≤ 0.5 mg/L	> 1 mg/L
1 Only uncomplicated urinary tract infections. 2 Susceptibility may be inferred from ciprofloxacin susceptibility.

The prevalence of resistance may vary geographically and over time for individual species; therefore, it is advisable to obtain local information on resistance, especially when treating severe infections. Advice from a specialist should be sought if local resistance patterns are such that the benefit of the medicinal product, at least for certain types of infections, is questionable.

Generally susceptible species

Aerobic Gram-positive bacteria: Bacillus anthracis, methicillin-susceptible Staphylococcus aureus, Staphylococcus saprophyticus, Streptococcus group C and G, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes.

Aerobic Gram-negative bacteria: Eikenella corrodens, Haemophilus influenzae, Haemophilus parainfluenzae, 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 resistance development

Aerobic Gram-positive bacteria: Enterococcus faecalis, methicillin-resistant* Staphylococcus aureus, 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.

Resistant strains

Aerobic Gram-positive bacteria: Enterococcus faecium.

* Methicillin-resistant Staphylococcus aureus is usually co-resistant to fluoroquinolones, including levofloxacin.

Pharmacokinetics.

Absorption

Orally administered levofloxacin is rapidly and almost completely absorbed, achieving peak plasma concentrations within 1–2 hours. Absolute bioavailability is 99–100%. Food has minimal effect on the absorption of levofloxacin. Steady state is reached within 48 hours with a dosing regimen of 500 mg once or twice daily.

Distribution

Approximately 30–40% of levofloxacin is bound to plasma proteins. The mean volume of distribution of levofloxacin is approximately 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 fluid), prostate tissue, and urine. However, penetration into cerebrospinal fluid is poor.

Biotransformation

Levofloxacin undergoes minimal metabolism, with metabolites being 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

Following both oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6–8 hours). Elimination occurs primarily via the kidneys (over 85% of the administered dose). The mean total 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 intravenous and oral administration, indicating interchangeability of these routes (oral and intravenous).

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 decreased renal function, renal excretion and clearance are reduced, and elimination half-life is prolonged, as shown in the table below.

Pharmacokinetics in renal impairment after a single 500 mg oral dose

Creatinine clearance (mL/min)	< 20	20–49	50–80
Renal clearance (mL/min)	13	26	57
Half-life (hours)	35	27	9

Geriatric patients

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

Gender differences

Separate analysis in male and female patients has shown minor differences in levofloxacin pharmacokinetics depending on gender. There is no evidence that gender differences are clinically significant.

Clinical characteristics.

Indications.

For use in adults for the treatment of the following infections (see sections "Special precautions for use" and "Pharmacodynamics"):

• acute pyelonephritis, complicated urinary tract infections (see section "Special precautions for use");
• chronic bacterial prostatitis.

For the following infections, levofloxacin should be used only when other antibacterial agents, usually recommended for treatment of these infections, are inappropriate:

• community-acquired pneumonia;
• complicated skin and soft tissue infections.

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

Contraindications.

− Hypersensitivity to levofloxacin, other quinolones, or to any of the excipients of the medicinal product;

− epilepsy;

− tendon-related adverse reactions following prior administration of fluoroquinolones;

− age under 18 years;

− pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on levofloxacin

Theophylline, fenbufen or similar nonsteroidal anti-inflammatory drugs (NSAIDs).

No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a marked reduction in seizure threshold may occur with concomitant administration of quinolones and theophylline, nonsteroidal anti-inflammatory drugs, or other agents that lower the seizure threshold. The concentration of levofloxacin was approximately 13% higher when administered with fenbufen than when levofloxacin was administered alone.

Probenecid and cimetidine

Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin. Renal clearance of levofloxacin is reduced by 24% in the presence of cimetidine and by 34% with probenecid, as both agents can block tubular secretion of levofloxacin. However, the statistically significant kinetic differences observed in studies are unlikely to be of clinical significance. Concomitant administration of levofloxacin with medicinal products affecting tubular secretion, such as probenecid and cimetidine, should be approached with caution, especially in patients with renal impairment.

Other important information

Pharmacological clinical studies have demonstrated that the following medicinal products do not have any clinically significant effect on the pharmacokinetics of levofloxacin: 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 administered concomitantly with vitamin K antagonists (e.g., warfarin), increased coagulation test parameters (prothrombin time (PT), international normalized ratio (INR)) and/or bleeding events, which may be severe, have been reported. Therefore, patients receiving vitamin K antagonists concurrently require monitoring of coagulation parameters (see section "Special precautions for use").

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, antipsychotics) (see section "Special precautions for use").

Other important information

Levofloxacin does not affect the pharmacokinetics of theophylline, a substrate of the CYP1A2 enzyme; therefore, levofloxacin is not considered to be an inhibitor of CYP1A2.

Special precautions for use.

Levofloxacin solution for intravenous administration should be used immediately (within 3 hours) after piercing the stopper to prevent bacterial contamination. Protection from light during infusion is not required. Before administration, the solution should be visually inspected. It may be used only if the solution is clear, yellow or greenish-yellow, and free from visible particles. The medicinal product packaging is intended for single use only. Unused residues should be disposed of according to local regulations.

Compatibility with other infusion solutions

Levofloxacin solution is compatible with the following infusion solutions:

• 0.9% sodium chloride solution;
• 5% glucose solution;
• 2.5% glucose in Ringer's solution;
• multi-component parenteral nutrition solutions (amino acids, carbohydrates, electrolytes).

Levofloxacin should be avoided in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones (see section "Adverse Reactions"). Treatment with levofloxacin in these patients should be initiated only if no alternative treatment options are available and after careful benefit-risk assessment (see section "Contraindications").

Resistance risk

For methicillin-resistant S. aureus (MRSA), there is a very high likelihood of co-resistance to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of infections where MRSA is known or suspected, except when laboratory test results confirm susceptibility of the pathogen to levofloxacin (and when recommended antibacterial agents for MRSA infection are considered inappropriate).

Resistance of E. coli (the most common pathogen in urinary tract infections) to fluoroquinolones varies across countries. Local prevalence of E. coli resistance to fluoroquinolones should be considered when prescribing the drug.

Pulmonary anthrax

Clinical experience is based on Bacillus anthracis in vitro susceptibility studies, animal experimental data, and limited human data. Physicians should refer to nationally and/or internationally agreed guidelines for the treatment of anthrax.

Long-term, disabling, and potentially irreversible serious adverse reactions

In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of age or risk factors, have experienced long-term (lasting several months or years), disabling, and potentially irreversible serious adverse reactions affecting various body systems (including musculoskeletal, nervous, psychiatric, and sensory systems). The drug should be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.

Duration of infusion

The infusion duration should be 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, a rapid drop in blood pressure may lead to cardiovascular failure. If a significant drop in blood pressure occurs during levofloxacin (L-isomer of ofloxacin) infusion, the drug administration should be stopped immediately.

Tendinitis and tendon rupture

Tendinitis and tendon rupture (particularly of the Achilles tendon), sometimes bilateral, may occur as early as 48 hours after initiation of quinolone or fluoroquinolone therapy and, in some cases, even several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with impaired renal function, transplant recipients, patients receiving daily doses exceeding 1000 mg, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided. Levofloxacin should be discontinued at the first signs of tendinitis (e.g., painful swelling, inflammation), and alternative treatment should be considered. The affected limb should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy occur.

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 impaired renal function if the levofloxacin dose is not adjusted according to creatinine clearance. Levofloxacin should be discontinued immediately upon the first occurrence of myoclonus, and appropriate treatment should be initiated.

Clostridium difficile-associated disease

Diarrhea, especially severe, persistent, and/or hemorrhagic, during or after treatment with levofloxacin (including several weeks after treatment) may indicate Clostridium difficile-associated disease. Clostridium difficile-associated diarrhea may range in severity from mild to life-threatening, with pseudomembranous colitis being the most severe form (see section "Adverse Reactions"). This diagnosis should be considered in patients who develop severe diarrhea during or after treatment with levofloxacin. If Clostridium difficile-associated disease is suspected or confirmed, levofloxacin should be discontinued immediately and appropriate treatment should be initiated. Antiperistaltic agents are contraindicated in this clinical situation.

Patients predisposed to seizures

Quinolones may lower the seizure threshold and provoke seizures. Levofloxacin is contraindicated in patients with a history of epilepsy and, like other quinolones, should be used with extreme caution in patients predisposed to seizures, such as those with central nervous system (CNS) disorders, concomitant use of phenylbutazone and similar nonsteroidal anti-inflammatory drugs, or drugs that lower the seizure threshold, such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If seizures occur, levofloxacin treatment should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or overt glucose-6-phosphate dehydrogenase deficiency may be susceptible to hemolytic reactions when treated with quinolone antibacterial agents; therefore, levofloxacin should be used with caution in these patients, with monitoring for possible hemolysis.

Patients with renal impairment

Since levofloxacin is primarily excreted by the kidneys, dose adjustment is required in patients with impaired renal function (renal insufficiency) (see section "Dosage and administration").

Hypersensitivity reactions

Levofloxacin may cause serious, potentially fatal hypersensitivity reactions (e.g., angioedema, anaphylactic shock), even after the first dose (see section "Adverse Reactions"). In such cases, patients should discontinue treatment immediately and seek medical attention for appropriate emergency measures.

Severe skin adverse reactions

Severe skin adverse reactions, including toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with levofloxacin use, which may be fatal (see section "Adverse Reactions"). Patients should be informed about the signs of severe skin reactions, and their condition should be closely monitored. If signs of such reactions occur, levofloxacin should be discontinued immediately, and alternative treatment should be considered. Patients who develop a serious skin reaction such as toxic epidermal necrolysis, Stevens-Johnson syndrome, or DRESS syndrome during levofloxacin treatment should never be re-treated with levofloxacin.

Disturbances in blood glucose

Disturbances in blood glucose levels, including both hypoglycemia and hyperglycemia, have been reported with quinolones, including levofloxacin, particularly in elderly patients and in diabetic patients receiving concomitant hypoglycemic agents (e.g., glyburide) or insulin. Cases of hypoglycemic coma have been reported. Close monitoring of blood glucose levels is recommended in diabetic patients (see section "Adverse Reactions"). If a patient reports disturbances in blood glucose levels, levofloxacin treatment should be discontinued immediately, and alternative non-fluoroquinolone antibacterial therapy should be considered.

Phototoxicity prevention

Cases of phototoxicity have been reported with levofloxacin (see section "Adverse Reactions"). To prevent phototoxicity, patients are advised to avoid exposure to strong sunlight or artificial UV radiation (including UV lamps, tanning beds) during treatment and for 48 hours after discontinuation of levofloxacin.

Patients receiving vitamin K antagonists

Due to the potential for increased coagulation test parameters (PT, INR) and/or bleeding in patients taking levofloxacin concomitantly with vitamin K antagonists (e.g., warfarin), coagulation test parameters should be monitored when these agents are used together (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 administration of only a single dose of levofloxacin (see section "Adverse Reactions"). If such reactions occur, levofloxacin should be discontinued and medical advice should be sought. Alternative non-fluoroquinolone therapy should be considered, and appropriate measures taken. Caution is recommended when using levofloxacin in patients with a history of psychotic or psychiatric disorders.

QT interval prolongation

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

• congenital long QT syndrome;
• concomitant use of medicinal products that can prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics);
• uncorrected electrolyte imbalance (e.g., hypokalemia, hypomagnesemia);
• heart disease (e.g., heart failure, myocardial infarction, bradycardia).

Elderly patients and women are more sensitive to drugs that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used with caution in these patient groups (see sections "Dosage and administration", "Overdose", "Interaction with other medicinal products and other forms of interaction", "Adverse Reactions").

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 immediately to prevent potentially irreversible damage (see section "Adverse Reactions").

Hepatobiliary disorders

Cases of necrotic hepatitis up to fatal hepatic failure have been reported with levofloxacin, primarily in patients with severe underlying conditions such as sepsis (see section "Adverse Reactions"). Patients should be advised to discontinue treatment and seek medical attention 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. Serious adverse reactions, including fatal cases and conditions requiring respiratory support, have been observed in patients with myasthenia gravis during post-marketing experience with fluoroquinolones. 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 treatment, patients should seek immediate medical attention (see sections "Effect on ability to drive and use machines" and "Adverse Reactions").

Superinfection

Use of levofloxacin, particularly prolonged use, may lead to overgrowth of non-susceptible (resistant) microorganisms. If superinfection occurs during treatment, appropriate measures should be taken.

Effect on laboratory test results

In patients taking levofloxacin, opiate screening in urine may yield false-positive results. Confirmation of a positive opiate test may require more specific methods.

Levofloxacin may inhibit the growth of Mycobacterium tuberculosis, thus leading to false-negative results in bacteriological diagnosis of tuberculosis.

Aortic aneurysm or dissection, valvular regurgitation/insufficiency

Epidemiological studies indicate an increased risk of aortic aneurysm and dissection, particularly in elderly patients, as well as an increased risk of aortic and mitral valve regurgitation following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and valvular regurgitation/insufficiency have been reported in patients taking fluoroquinolones (see section "Adverse Reactions"). Therefore, fluoroquinolones should be used only after careful benefit-risk assessment and consideration of alternative treatment options in patients with:

• family history of aneurysm or congenital heart valve defects;

• established diagnosis of aortic aneurysm or aortic dissection;

• diagnosed heart valve disease;

• other risk factors, including:

  • risk factors for aortic aneurysm, aortic dissection, or valvular 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, giant cell arteritis, atherosclerosis, Sjögren's syndrome;
  • risk factors for valvular regurgitation/insufficiency: infective endocarditis.

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

Patients should seek immediate emergency medical attention if sudden abdominal, chest, or back pain occurs.

Patients should also be advised to seek immediate medical help if acute dyspnea, sudden 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 characteristic 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; if the diagnosis is confirmed, levofloxacin should not be restarted. Caution should be exercised in patients with a history of pancreatitis (see section "Adverse Reactions").

Blood disorders

Bone marrow suppression, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, or agranulocytosis, may develop during levofloxacin treatment (see section "Adverse Reactions"). If any of these disorders are suspected, blood parameters should be monitored. If abnormalities are detected, discontinuation of levofloxacin should be considered.

Sodium content

This medicinal product contains 15.43 mmol (or 354.7 mg) of sodium per 100 ml. Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of levofloxacin in pregnant women are limited. Animal studies have not shown direct or indirect harmful effects on reproductive function. However, due to the lack of human data and experimental evidence of risk of cartilage damage in the developing organism by fluoroquinolones, levofloxacin is contraindicated in pregnant women (see section "Contraindications").

Breastfeeding. Levofloxacin is contraindicated in women who are breastfeeding. There is insufficient information on whether levofloxacin passes into breast milk; however, other fluoroquinolones do penetrate into breast milk. Due to the lack of human data and experimental evidence of risk of cartilage damage in the developing organism by fluoroquinolones, levofloxacin is contraindicated in breastfeeding women (see section "Contraindications").

Fertility. Levofloxacin did not impair fertility or reproductive performance in rats.

Effect on ability to drive and use machines.

Levofloxacin has a minor or moderate effect on the ability to drive and operate machinery. Some adverse reactions (e.g., dizziness/vertigo, somnolence, visual and hearing disturbances) may impair the ability to concentrate and react quickly, thus posing a risk in situations where these abilities are particularly important (e.g., driving a car or operating machinery).

Dosage and administration.

The medicinal product is administered by slow intravenous infusion once or twice daily. The dosage depends on the type and severity of the infection, as well as the susceptibility of the likely pathogen to the drug. After initial intravenous therapy with levofloxacin, treatment may be completed with oral levofloxacin according to the instructions for medical use and depending on the patient's condition. Due to the bioequivalence of the parenteral and oral forms, the same dosage may be used.

Dosage

Dosage in patients with normal renal function (creatinine clearance > 50 mL/min)

Indications	Daily dosage	Duration of treatment*
Community-acquired pneumonia	500 mg 1–2 times/day	7–14 days
Acute pyelonephritis	500 mg once daily	7–10 days
Complicated urinary tract infections	500 mg once daily	7–14 days
Chronic bacterial prostatitis	500 mg once daily	28 days
Complicated skin and soft tissue infections	500 mg 1–2 times/day	7–14 days
* Duration of treatment includes intravenous and oral administration. The time to switch from intravenous to oral administration depends on the clinical situation, but usually takes 2–4 days.

Since levofloxacin is primarily excreted by the kidneys, the dose should be reduced in patients with impaired renal function.

Use in special patient groups

Patients with renal impairment (creatinine clearance < 50 ml/min)

Creatinine clearance	Dosing regimen
	250 mg/24 h	500 mg/24 h	500 mg/12 h
	first dose: 250 mg	first dose: 500 mg	first dose: 500 mg
50–20 mL/min	then: 125 mg/24 h	then: 250 mg/24 h	then: 250 mg/12 h
19–10 mL/min	then: 125 mg/48 h	then: 125 mg/24 h	then: 125 mg/12 h
<10 mL/min (also during hemodialysis and CAPD*)	then: 125 mg/48 h	then: 125 mg/24 h	then: 125 mg/24 h
* After hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), additional doses are not required.

Patients with hepatic impairment

Dose adjustment is not required, since levofloxacin is minimally metabolized in the liver and is primarily excreted by the kidneys.

Elderly patients

Dose adjustment is not required in elderly patients, except in cases of renal impairment (see also the sections «Special precautions» subsections «Tendinitis and tendon rupture» and «QT interval prolongation»).

Method of administration

The solution should be administered only by slow intravenous infusion once or twice daily. The duration of infusion should be at least 30 minutes for the 250 mg dose and at least 60 minutes for the 500 mg dose.

Children

Levofloxacin is contraindicated in children under 18 years of age.

Overdose

Based on the results of toxicity studies in animals and clinical pharmacology studies using supratherapeutic doses, the most significant symptoms expected following acute levofloxacin overdose are central nervous system (CNS) effects such as confusion, dizziness, altered consciousness, and seizures, as well as QT interval prolongation. During post-marketing use, CNS effects including confusion, seizures, myoclonus, hallucinations, and tremor have been observed.

In case of overdose, symptomatic treatment should be administered. Continuous ECG monitoring is also required due to the potential for QT interval prolongation. Hemodialysis, including peritoneal dialysis and hemoperfusion, is not effective in removing levofloxacin from the body. There is no specific antidote.

Adverse Reactions

The frequency of adverse reactions is defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Infections and infestations. Uncommon: fungal infections, including infections caused by Candida species. Resistance of pathogenic microorganisms.

Blood and lymphatic system disorders. Uncommon: leucopenia, eosinophilia. Rare: thrombocytopenia, neutropenia. Frequency not known: bone marrow depression, including aplastic anaemia, pancytopenia, agranulocytosis, haemolytic anaemia.

Immune system disorders. Rare: Quincke's oedema, hypersensitivity. Frequency not known: anaphylactic shock, anaphylactoid shock (may occasionally occur even after administration of the first dose).

Endocrine system disorders. Rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders. Uncommon: anorexia. Rare: hypoglycaemia, especially in patients with diabetes mellitus, hypoglycaemic coma. Frequency not known: hyperglycaemia.

Psychiatric disorders*. Common: insomnia. Uncommon: anxiety, confusion, restlessness. Rare: psychotic disorders (e.g. with hallucinations, paranoia), depression, agitation, sleep disturbances, nightmares, delirium. Frequency not known: mania, psychotic reactions with self-destructive behaviour, including suicidal thoughts and suicide attempts.

Nervous system disorders*. Common: headache, dizziness. Uncommon: somnolence, tremor, dysgeusia. Rare: seizures, paraesthesia, memory impairment. Frequency not known: myoclonus, sensory or sensorimotor peripheral neuropathy; parosmia, including anosmia; dyskinesia, extrapyramidal disorders, ageusia, loss of consciousness, benign intracranial hypertension.

Eye disorders*. Rare: visual disturbances, e.g. blurred vision. Frequency not known: transient loss of vision, uveitis.

Ear and labyrinth disorders*. Uncommon: vertigo. Rare: tinnitus. Frequency not known: hearing loss, disturbances of hearing.

Cardiac disorders**. Rare: tachycardia, palpitations. Frequency not known: ventricular tachycardia, which may lead to cardiac arrest, ventricular arrhythmia and torsade de pointes (mainly in patients with risk factors for QT interval prolongation), QT interval prolongation, as observed on electrocardiogram.

Vascular disorders**. Common: phlebitis (only with intravenous formulations). Rare: arterial hypotension.

Respiratory, thoracic and mediastinal disorders. Uncommon: dyspnoea. Frequency not known: bronchospasm, allergic pneumonitis.

Gastrointestinal disorders. Common: diarrhoea, vomiting, nausea. Uncommon: abdominal pain, dyspepsia, bloating, constipation. Frequency not known: haemorrhagic diarrhoea, which rarely may indicate enterocolitis, including pseudomembranous colitis, pancreatitis.

Hepatobiliary disorders. Common: increased liver enzyme levels (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamyl transferase (GGT)). Uncommon: increased blood bilirubin. Frequency not known: jaundice and severe hepatic injury, including fatal cases of acute liver failure, mainly in patients with severe underlying diseases, hepatitis.

Skin and subcutaneous tissue disorders. Uncommon: rash, pruritus, urticaria, hyperhidrosis. Rare: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), fixed drug eruption. Frequency not known: toxic epidermal necrolysis, Stevens-Johnson syndrome, polymorphic erythema, photosensitivity reactions, leukocytoclastic vasculitis, skin hyperpigmentation, stomatitis. Skin disorders may occasionally occur even after administration of the first dose.

Musculoskeletal and connective tissue disorders*. Uncommon: arthralgia, myalgia. Rare: tendon disorders, including tendinitis (e.g. Achilles tendon), muscle weakness, which may be particularly significant in patients with myasthenia gravis. Frequency not known: acute skeletal muscle necrosis (rhabdomyolysis), tendon rupture (e.g. Achilles tendon), ligament rupture, muscle rupture, arthritis.

Renal and urinary disorders. Uncommon: increased serum creatinine levels. Rare: acute renal failure (e.g. due to interstitial nephritis).

General disorders and administration site conditions*. Common: infusion site reaction (pain, redness). Uncommon: asthenia. Rare: pyrexia. Frequency not known: pain (including back, chest and extremity pain).

Other adverse reactions associated with fluoroquinolone use: acute attacks of porphyria in patients with porphyria.

* In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of age and presence of risk factors, have experienced long-term (lasting several months or years), disabling and potentially irreversible serious adverse reactions affecting various organ systems (including tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, paraesthesia and neuropathic neuralgia, fatigue, psychiatric symptoms (including sleep disturbances, anxiety, panic attacks, depression and suicidal thoughts), memory and concentration impairment, disturbances of hearing, vision, taste and smell).

** Cases of aortic aneurysm or dissection, sometimes complicated by rupture (including fatal cases), and cases of regurgitation/insufficiency of any cardiac valve have been reported in patients receiving fluoroquinolones (see section "Special precautions for use").

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C, protected from light and out of reach of children.

Incompatibilities. Levofloxacin must not be mixed with heparin or alkaline solutions (e.g. sodium bicarbonate), or with other medicinal products except those specified in the section "Special precautions for use".

Packaging. 100 ml or 150 ml in a bottle; 1 bottle in a carton.

Prescription category. Prescription only.

Manufacturer. Private Joint-Stock Company "Infuziya".

Manufacturer's address and location of operations.

84A Nemirivske Shose, Vinnytski Khutory, Vinnytsia district, Vinnytsia region, 23219, Ukraine.

Marketing Authorisation Holder. Private Joint-Stock Company "Infuziya".

Address of the Marketing Authorisation Holder and/or its representative.

21-A Moskovskyi Avenue, Kyiv, 04073, Ukraine.