Levopro

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

Composition:

Active substance: levofloxacin;

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

Excipients: sodium chloride, edetate disodium, diluted hydrochloric acid, 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. Antibacterial agents of the quinolone group. Fluoroquinolones.

ATC code J01M A12.

Pharmacological properties

Pharmacodynamics.

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

Mechanism of action

As an antibacterial agent from the fluoroquinolone group, levofloxacin acts on the DNA-DNA gyrase and topoisomerase IV complex.

Pharmacokinetic/pharmacodynamic relationship

The extent of antibacterial activity of levofloxacin depends on the ratio of maximum serum concentration (C_max) or area under the pharmacokinetic curve (AUC) to 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 for Pseudomonas aeruginosa) and efflux mechanisms, may also affect susceptibility to levofloxacin.

Cross-resistance between levofloxacin and other fluoroquinolones is observed. Due to its mechanism of action, there is no cross-resistance between levofloxacin and other classes of antibacterial agents.

Breakpoints

The recommended breakpoints for levofloxacin, as defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which distinguish susceptible microorganisms from intermediate (moderately resistant) organisms and intermediate from resistant organisms, are presented in the MIC testing table below (mg/L).

Clinical MIC breakpoints for levofloxacin as defined by EUCAST [European Committee on Antimicrobial Susceptibility Testing] (version 10.0, 01-01-2020)

Table 1

Pathogens	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	≤ 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 urinae 2	≤ 2 mg/l	> 2 mg/l
Aeromonas spp.	≤ 0.5 mg/l	> 1 mg/l
Interim non-species-related values 4	≤ 0.5 mg/l	> 1 mg/l

1 Uncomplicated urinary tract infections only.

2 Susceptibility conclusion can be based on susceptibility to ciprofloxacin.

The prevalence of resistance among individual species may vary geographically and over time; therefore, local information on resistance should be obtained, especially when treating severe infections. Advice from a specialist should be sought if local resistance prevalence renders the benefit of the drug at least questionable for certain types of infections.

Usually 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 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 acquired (secondary) resistance issues

Aerobic Gram-positive bacteria:

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

Gram-positive aerobes:

Enterococcus faecium.

* Methicillin-resistant S. aureus may exhibit resistance to fluoroquinolones, including levofloxacin.

Pharmacokinetics.

Absorption

After oral administration, levofloxacin is rapidly and almost completely absorbed, reaching peak plasma concentrations within 1–2 hours. Absolute bioavailability is 99–100%.

Food has minimal effect on levofloxacin absorption.

Steady state is 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 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, alveolar 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). 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 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.

Special populations

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:

Table 2

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 in younger and elderly patients, except for differences related to creatinine clearance.

Gender differences

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

Clinical characteristics.

Indications.

Administer to adults for the treatment of infections caused by microorganisms sensitive to the drug (see sections "Pharmacodynamics", "Special precautions"):

• Community-acquired pneumonia;
• Complicated skin and soft tissue infections

(For the above-mentioned infections, the medicinal product should be used only when other antibacterial agents, which are usually recommended for initial treatment of these infections, are inappropriate or impossible to use);

• Acute pyelonephritis, complicated urinary tract infections (see section "Special precautions");
• Chronic bacterial prostatitis;
• Pulmonary form of anthrax: post-exposure prophylaxis and definitive treatment (see section "Special precautions").

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

Contraindications.

• Hypersensitivity to levofloxacin, other fluoroquinolones, or to excipients of the medicinal product.
• Epilepsy.
• Tendon disorders related to prior use of fluoroquinolones.
• Pediatric age (under 18 years).
• Pregnancy.
• 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 was observed. However, a significant reduction in seizure threshold may occur with concomitant administration of quinolones with theophylline, NSAIDs, and other agents that reduce seizure threshold. Levofloxacin concentrations were approximately 13% higher in the presence of fenbufen compared to levofloxacin alone.

Probenecid and cimetidine

Probenecid and cimetidine significantly affect the elimination of levofloxacin. Renal clearance of levofloxacin decreases by 24% with cimetidine and by 34% with probenecid, as both drugs can block tubular secretion of levofloxacin. However, at the doses tested in the study, it is unlikely that statistically significant kinetic differences would have clinical relevance. Levofloxacin should be used with caution together with medicinal products affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other information

Clinical pharmacology studies have demonstrated no clinically significant effect on the pharmacokinetics of levofloxacin when administered concomitantly with the following medicinal products: calcium carbonate, digoxin, glyburide, ranitidine.

Effect of Levopro 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 coagulation test parameters (prothrombin time [PT]/international normalized ratio [INR]) and/or bleeding, which may be severe, have been reported. Therefore, coagulation parameters should be monitored when these agents are used concomitantly (see section "Special precautions").

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. QT interval prolongation").

Other important information

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

Special precautions for use.

Avoid administering the drug to patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones. Treatment with levofloxacin in such patients should be initiated only if no alternative treatment options are available and after careful benefit/risk assessment (see section "Contraindications").

Use in infections caused by methicillin-resistant Staphylococcus aureus (MRSA)

Methicillin-resistant Staphylococcus aureus is highly likely to exhibit cross-resistance to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of infections known or suspected to be caused by MRSA, except when laboratory testing confirms susceptibility of the pathogen to levofloxacin (and when standard antibacterial agents for MRSA infections are unsuitable).

Use in infections caused by E. coli

Resistance of E. coli (the most common causative agent of urinary tract infections) to fluoroquinolones varies across different countries. When prescribing the drug, local prevalence of E. coli resistance to fluoroquinolones should be taken into account.

Use in pulmonary anthrax

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

Prolonged, disabling, and potentially irreversible serious adverse reactions

Very rarely, in patients receiving quinolones and fluoroquinolones, regardless of age and existing risk factors, prolonged (lasting several months or years), disabling, and potentially irreversible serious adverse reactions affecting various systems (sometimes multiple simultaneously), including musculoskeletal, nervous system, mental health, and sensory organs, have been reported. At the first sign or symptom of any serious adverse reaction, administration of the drug should be immediately discontinued and medical advice sought.

Duration of infusion

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

Sodium content should be considered for patients on a sodium-controlled diet.

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, according to reports, even several months after discontinuation of treatment in patients receiving 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 corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.

At the first signs of tendinitis (e.g., painful swelling, inflammation), treatment with the drug 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 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 renal impairment if the levofloxacin dose is not adjusted according to creatinine clearance. Upon first occurrence of myoclonus, levofloxacin should be immediately discontinued and appropriate treatment initiated.

Clostridium difficile-associated disease

Diarrhea, particularly severe, persistent, and/or hemorrhagic, during or after levofloxacin treatment (including several weeks after treatment) may be a symptom of disease caused by Clostridium difficile, the most severe form of which is pseudomembranous colitis (see section "Adverse reactions"). This diagnosis should be considered in patients who develop severe diarrhea during or after levofloxacin therapy. If pseudomembranous colitis is suspected, levofloxacin infusion should be immediately discontinued and appropriate treatment initiated promptly. Antiperistaltic agents are contraindicated in this clinical situation.

Patients predisposed to seizures

Quinolones may lower the seizure threshold and provoke seizures.

Levopro, infusion solution, is contraindicated in patients with a history of epilepsy (see section "Contraindications") and, like other quinolones, should be used with extreme caution in patients predisposed to seizures, such as those with prior central nervous system (CNS) disorders, or those receiving concomitant medications that lower the cerebral seizure threshold, such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If seizures occur (see section "Adverse reactions"), 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-class antibacterial agents. Therefore, the drug should be used with caution in such patients, and monitoring for possible hemolysis is recommended.

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 "Method of administration and dosage").

Hypersensitivity reactions

Levofloxacin may occasionally cause serious, potentially life-threatening hypersensitivity reactions (e.g., angioedema, up to anaphylactic shock), sometimes after administration of the initial dose (see section "Adive reactions"). If such reactions occur, the drug should be immediately discontinued and medical advice sought.

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 syndrome), have been reported with levofloxacin use, which may be life-threatening or even fatal (see section "Adverse reactions"). When prescribing the drug, patients should be warned about signs and symptoms of severe skin reactions and kept under close monitoring. If signs or symptoms indicating these reactions appear, levofloxacin should be immediately discontinued and alternative therapy considered. If a patient develops a serious skin reaction such as toxic epidermal necrolysis, Stevens-Johnson syndrome, or DRESS syndrome during levofloxacin treatment, levofloxacin therapy should never be restarted in such a patient.

Disturbances in blood glucose

As with other quinolones, disturbances in blood glucose levels, including both hypoglycemia and hyperglycemia, have been reported, usually in diabetic patients receiving concomitant therapy with hypoglycemic agents (e.g., glibenclamide) or insulin. Cases of hypoglycemic coma have been documented. When using the drug in diabetic patients, careful monitoring of plasma glucose levels is recommended (see section "Adverse reactions").

If a patient reports disturbances in plasma glucose levels, treatment should be immediately discontinued and alternative antibacterial therapy with non-fluoroquinolone agents considered.

Prevention of photosensitization

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

Patients receiving vitamin K antagonists

There is a possibility of increased coagulation test results (PT/INR) and/or bleeding in patients taking levofloxacin concomitantly with vitamin K antagonists (e.g., warfarin). Therefore, when these agents are used together, monitoring of coagulation test parameters is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Psychotic reactions

Psychotic reactions have been reported in patients receiving quinolones, including levofloxacin. Very rarely, these progressed to suicidal thoughts and self-harming behavior, sometimes after only a single dose of levofloxacin (see section "Adverse reactions"). If such reactions occur in a patient, levofloxacin should be discontinued and appropriate measures taken. Caution is recommended when prescribing levofloxacin to patients with psychotic disorders or psychiatric history.

QT interval prolongation

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

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

Elderly patients and women may be more sensitive to drugs that prolong the QT interval. Therefore, caution is required when using fluoroquinolones, including levofloxacin, in these patient groups (see sections "Method of administration and dosage. Dosage in elderly patients", "Interaction with other medicinal products and other forms of interaction", "Adverse reactions", "Overdose").

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 be advised to inform their physician promptly to prevent potentially irreversible damage (see section "Adverse reactions").

Hepatobiliary disorders

Cases of necrotic hepatitis up to life-threatening liver failure have been reported with levofloxacin use, primarily in patients with severe underlying conditions, such as sepsis (see section "Adverse reactions"). Patients should be advised to discontinue treatment and consult a physician 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 cases and conditions requiring respiratory support, have been reported in patients with myasthenia gravis receiving fluoroquinolones. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances

If any visual disturbances or adverse reactions affecting the eyes occur during levofloxacin use, immediate medical advice should be sought (see sections "Ability to influence reaction rate when driving or operating machinery" and "Adverse reactions").

Superinfection

Use of levofloxacin, especially prolonged use, may lead to overgrowth of organisms 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 testing may yield false-positive results. Confirmation of positive opiate test results using more specific methods may be necessary.

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

Aortic aneurysm or dissection and cardiac valve regurgitation/insufficiency

Epidemiological studies indicate 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 therapies in patients with:

• positive family history of aneurysm or congenital heart valve disease, or diagnosed aortic aneurysm and/or dissection and/or heart valve disease, or presence of risk factors or conditions predisposing to:
• both aortic aneurysm and dissection and cardiac valve regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, arterial hypertension, rheumatoid arthritis), or additionally:
• aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren's syndrome), or additionally:
• cardiac valve regurgitation/insufficiency (e.g., infective endocarditis).

The risk of aortic aneurysm and dissection and their rupture may also be increased in patients receiving systemic corticosteroids concomitantly.

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

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

Acute pancreatitis

Acute pancreatitis may occur in patients receiving levofloxacin. Patients should be informed about the characteristic symptoms of acute pancreatitis. Patients who develop nausea, malaise, abdominal discomfort, acute abdominal pain, or vomiting should be evaluated immediately. If acute pancreatitis is suspected, the drug should be discontinued. Re-administration of levofloxacin is not permitted if the diagnosis is confirmed. The drug should be used with caution in patients with a history of pancreatitis (see section "Adverse reactions").

Disorders of the blood

Bone marrow suppression, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, or agranulocytosis, may develop during levofloxacin therapy (see section "Adverse reactions"). If any of these disorders is suspected, blood test results should be monitored. If abnormal results are obtained, discontinuation of levofloxacin therapy should be considered.

Use during pregnancy or breastfeeding.

Pregnancy.

Data on the use of levofloxacin in pregnant women are limited. Animal studies do not indicate direct or indirect reproductive toxicity (see section "Pharmacological properties"). Due to the lack of human studies and the potential for quinolones to damage articular cartilage in the growing organism, the drug is contraindicated during pregnancy (see section "Contraindications").

Period of breastfeeding.

Levofloxacin is contraindicated in women who are breastfeeding. Information on the passage of levofloxacin into breast milk is insufficient, although it is known that other fluoroquinolones are excreted in breast milk. Due to the lack of human studies and the potential for fluoroquinolones to damage articular cartilage in the growing organism, the drug is contraindicated during breastfeeding (see sections "Contraindications" and "Pharmacological properties").

Fertility.

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

Ability to influence reaction rate when driving or operating machinery.

Levofloxacin has a minor or moderate influence on the ability to drive and operate machinery. Some adverse reactions (e.g., dizziness/vertigo, somnolence, visual disturbances) may reduce a patient's ability to concentrate and reaction speed, thereby increasing the risk in situations where these abilities are particularly important (e.g., driving a car or operating machinery).

Administration and Dosage

The intravenous preparation should be used within 3 hours after piercing the rubber stopper. Protection from light during infusion is not required. The solution for intravenous administration may be stored under room lighting for up to 3 days without protection from light.

The drug should be 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 causative organism to the drug.

It is possible to switch from initial intravenous administration of levofloxacin to oral administration according to the instructions for medical use of levofloxacin tablets, depending on the patient's condition. Due to the bioequivalence of oral and parenteral forms, the dosage may remain the same.

For treatment of adults with normal renal function, in whom creatinine clearance is over 50 mL/min, the recommended doses of the drug are as follows:

Table 3

Indications	Daily dose (depending on severity)	Duration of treatment* (depending on severity)
Community-acquired pneumonia	500 mg once or twice daily	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 once or twice daily	7–14 days
Pulmonary form of anthrax	500 mg once daily	8 weeks

* Duration of treatment includes both intravenous and oral administration of the medicinal product. The time of transition from intravenous to oral administration depends on the clinical condition, but usually takes from 2 to 4 days.

Dosing for adult patients with renal function impairment, in whom creatinine clearance is less than 50 ml/min:

Table 4

Dosing regimen
Creatinine clearance	250 mg/24 hours	500 mg/24 hours	500 mg/12 hours
50–20 mL/min	initial dose – 250 mg subsequent – 125 mg/24 hours	initial dose – 500 mg subsequent – 250 mg/24 hours	initial dose – 500 mg subsequent – 250 mg/12 hours
19–10 mL/min	initial dose – 250 mg subsequent – 125 mg/48 hours	initial dose – 500 mg subsequent – 125 mg/24 hours	initial dose – 500 mg subsequent – 125 mg/12 hours
<10 mL/min (as well as during hemodialysis and CAPD1)	initial dose – 250 mg subsequent – 125 mg/48 hours	initial dose – 500 mg subsequent – 125 mg/24 hours	initial dose – 500 mg subsequent – 125 mg/24 hours

1 After hemodialysis or continuous ambulatory peritoneal dialysis (CAPD), additional doses are not required.

Dosage in patients with hepatic impairment.

Dose adjustment is not necessary in these patients, since levofloxacin is minimally metabolized in the liver and is primarily excreted via the kidneys.

Dosage in elderly patients.

If renal function is not impaired, dose adjustment is not required (see section "Special warnings and precautions for use", subsections "Tendinitis and tendon rupture" and "QT interval prolongation").

Method of administration

Levopro, solution for infusion, is administered as a slow intravenous infusion; the solution should be infused once or twice daily. The duration of infusion should be at least 30 minutes for the 250 mg dose or at least 60 minutes for the 500 mg dose (see section "Special warnings and precautions for use").

The duration of treatment depends on the course of the disease. As with other antibacterial agents, it is recommended to continue treatment with Levopro for at least 48–72 hours after normalization of body temperature or until microbiological confirmation of eradication of the causative organism.

Children

The use of this medicinal product is contraindicated in children and adolescents (under 18 years of age) (see section "Contraindications").

Overdose

Based on results from animal toxicity studies and clinical pharmacological studies using doses exceeding the therapeutic dose, the most significant expected symptoms of levofloxacin overdose involve the central nervous system (CNS), such as confusion and altered consciousness, dizziness, seizures, hallucinations, tremor, and QT interval prolongation.

During post-marketing surveillance, the following CNS adverse reactions have been observed: confusion, seizures, myoclonus, hallucinations, and tremor.

In case of overdose, symptomatic therapy should be applied according to clinical manifestations. Close monitoring of the patient, including ECG monitoring, should be performed due to the potential for QT interval prolongation. Hemodialysis, including peritoneal dialysis or CAPD, is not effective in removing levofloxacin from the body. There are no specific antidotes available.

Adverse Reactions

The information below is based on clinical trial data involving more than 8,300 patients and extensive post-marketing experience.

Adverse reactions are categorized as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), and frequency not known (cannot be estimated from available data).

Within each group, adverse reactions are listed in order of decreasing severity.

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

Blood and lymphatic system disorders. Uncommon: leukopenia, eosinophilia. Rare: thrombocytopenia, neutropenia. Frequency not known: bone marrow failure, including aplastic anemia, pancytopenia, agranulocytosis, hemolytic anemia.

Immune system disorders. Rare: hypersensitivity reactions, including angioedema (see section "Special Warnings and Precautions for Use"). Frequency not known: anaphylactic shock, anaphylactoid reactions (see section "Special Warnings and Precautions for Use").

Metabolism and nutrition disorders. Uncommon: anorexia. Rare: hypoglycemia, especially in patients with diabetes mellitus, hypoglycemic coma (see section "Special Warnings and Precautions for Use"). Frequency not known: hyperglycemia (see section "Special Warnings and Precautions for Use").

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: psychotic reactions with self-destructive behavior, including suicidal ideation and suicide attempts (see section "Special Warnings and Precautions for Use"), mania.

Nervous system disorders*. Common: headache, dizziness. Uncommon: somnolence, tremor, dysgeusia. Rare: seizures (see sections "Contraindications" and "Special Warnings and Precautions for Use"), paresthesia, memory impairment. Frequency not known: peripheral sensory or sensorimotor neuropathy (see section "Special Warnings and Precautions for Use"), olfactory disturbances (parosmia), including anosmia (loss of smell), dyskinesia (movement coordination disorders), extrapyramidal disorders, ageusia (loss of taste), syncope (fainting), benign intracranial hypertension, myoclonus.

Eye disorders*. Rare: visual disturbances, such as blurred vision (see section "Special Warnings and Precautions for Use"). Frequency not known: transient loss of vision (see section "Special Warnings and Precautions for Use"), uveitis.

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

Cardiac disorders**. Rare: tachycardia, palpitations. Frequency not known: ventricular tachycardia, which may lead to cardiac arrest, ventricular arrhythmia and torsades de pointes (mainly in patients with risk factors for QT interval prolongation), QT interval prolongation observed on ECG (see sections "Special Warnings and Precautions for Use" and "Overdose").

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

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

Gastrointestinal disorders. Common: diarrhea, vomiting, nausea. Uncommon: abdominal pain, dyspepsia, bloating, constipation. Frequency not known: hemorrhagic diarrhea, which rarely may indicate enterocolitis, including pseudomembranous colitis (see section "Special Warnings and Precautions for Use"), pancreatitis (see section "Special Warnings and Precautions for Use").

Hepatobiliary and biliary tract disorders. Common: increased liver enzyme levels (ALT/AST, alkaline phosphatase, GGT). Uncommon: increased blood bilirubin. Frequency not known: jaundice and severe hepatic injury, including fatal cases of acute liver failure, mainly in patients with serious underlying conditions (see section "Special Warnings and Precautions for Use"), hepatitis.

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

Skin and subcutaneous tissue disordersb. Uncommon: rash, pruritus, urticaria, hyperhidrosis. Rare: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special Warnings and Precautions for Use"), fixed drug eruption. Frequency not known: toxic epidermal necrolysis, Stevens-Johnson syndrome, polymorphic erythema, photosensitivity reactions (see section "Special Warnings and Precautions for Use"), leukocytoclastic vasculitis, stomatitis, skin hyperpigmentation.

Musculoskeletal and connective tissue disorders*. Uncommon: arthralgia, myalgia. Rare: tendon disorders (see sections "Contraindications" and "Special Warnings and Precautions for Use"), including tendinitis (e.g., Achilles tendon), muscle weakness, which may be particularly significant in patients with myasthenia (see section "Special Warnings and Precautions for Use"). Frequency not known: acute skeletal muscle necrosis (rhabdomyolysis), tendon rupture (e.g., Achilles tendon) (see sections "Contraindications" and "Special Warnings and Precautions for Use"), 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 (with intravenous administration). Uncommon: asthenia. Rare: fever. Frequency not known: pain (including back, chest, and limb pain).

Other adverse effects associated with the use of fluoroquinolones include:

• Porphyria attacks in patients with known porphyria; anxiety, suicidal thoughts, panic attacks, neuralgia, and attention disturbances, which may be manifestations of prolonged and disabling adverse reactions caused by fluoroquinolones.

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

b Skin and mucous membrane reactions may sometimes occur even after the first dose.

* In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of age or risk factors, have experienced prolonged (lasting several months or years), disabling, and potentially irreversible serious adverse reactions affecting various (sometimes multiple simultaneously) organ systems and sensory organs (including reactions such as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disturbances, hearing, vision, taste, and smell disturbances).

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

Incompatibility.

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 "Dosage and Administration".

Mixing with other infusion solutions

Levofloxacin is compatible with the following infusion solutions:

• 0.9% sodium chloride solution;
• 5% glucose monohydrate solution;
• multi-component parenteral nutrition solutions (amino acids, carbohydrates, electrolytes).

Shelf life. 3 years.

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

Packaging. 100 ml or 150 ml in a bottle, 1 bottle per carton.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Infuziya".

Manufacturer's address and location of operations.

Ukraine, 21034, Vinnytsia, Voloshkova St., 55

or

Ukraine, 23219, Vinnytsia Oblast, Vinnytsia Raion, village Vinnitski Khutory, Nemirovskе Highway, 84A.

Marketing Authorization Holder. Limited Liability Company "ES FARMA".

Address of the Marketing Authorization Holder.

Ukraine, 01010, Kyiv, Ivan Mazepa St., 3, office 174.