Levocin-n

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVOCIN-N (LEVOCIN-N)

Composition:

Active substance: levofloxacin;

100 ml of solution contain levofloxacin 500 mg;

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

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear greenish-yellow solution.

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. As a fluoroquinolone antibacterial agent, levofloxacin 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 a stepwise process of mutations in the target site of both types of topoisomerase II: DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as restricted penetration (common in Pseudomonas) and efflux mechanisms, may also affect susceptibility to levofloxacin.

Cross-resistance between levofloxacin and other fluoroquinolones has been established.

Due to its mechanism of action, cross-resistance between levofloxacin and other classes of antibacterial agents is generally not observed.

Breakpoints

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

Table 1

EUCAST clinical MIC breakpoints for levofloxacin (version 10.0, 01-01-2020)

1 Uncomplicated urinary tract infections only

2 Susceptibility may be inferred from sensitivity to ciprofloxacin

Resistance prevalence may vary geographically and over time for selected species. Local information on resistance should be obtained, especially when treating severe infections. Advice from a specialist should be sought when local resistance prevalence renders the utility of the agent at least questionable for certain types of infections.

Antibacterial spectrum

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 for which acquired (secondary) resistance may be problematic

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 highly likely to exhibit co-resistance to fluoroquinolones, including levofloxacin.

Pharmacokinetics.

Absorption

After oral administration, levofloxacin is rapidly and almost completely absorbed; Cmax is reached within 1–2 hours after dosing. Absolute bioavailability is approximately 99–100%. Food has minimal effect on the absorption of levofloxacin. Steady state is achieved within 48 hours with a dosing regimen of 500 mg once or twice daily.

Distribution

Approximately 30–40% of levofloxacin is bound to serum proteins. The mean volume of distribution of levofloxacin is approximately 100 L after a single dose and 500 mg repeated doses, indicating extensive distribution into body tissues.

Penetration into tissues and body fluids

Levofloxacin has demonstrated penetration into bronchial mucosa, bronchial secretions, lung tissue, alveolar macrophages, lung parenchyma, skin (bulla fluid), prostate tissue, and urine. However, levofloxacin penetrates poorly into cerebrospinal fluid.

Biotransformation

Levofloxacin is metabolized to a very small extent; metabolites include desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the amount of drug excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.

Elimination

Following oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6–8 hours). It is primarily eliminated via the kidneys (over 85% of the administered dose).

Linearity

Levofloxacin follows linear pharmacokinetics in the range of 50–1000 mg.

Patients with renal impairment

The pharmacokinetics of levofloxacin are influenced by the degree of renal impairment. With reduced renal function, renal elimination and clearance decrease, and elimination half-life increases (see Table 2).

Table 2

Pharmacokinetics in renal impairment after a single 500 mg dose of levofloxacin

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

Clinical characteristics.

Indications.

Levocin-N, infusion solution, is indicated in adults for the treatment of the following infectious diseases caused by microorganisms sensitive to levofloxacin, such as:

• community-acquired pneumonia*;
• complicated skin and soft tissue infections*;
• acute pyelonephritis and complicated urinary tract infections;
• chronic bacterial prostatitis;
• pulmonary form of anthrax: post-exposure prophylaxis and treatment.

* For the above-mentioned infectious diseases, levofloxacin should be prescribed only if it has been determined that other antibacterial agents typically used to treat these infections are ineffective or inappropriate.

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

Contraindications.

Levocin-N, infusion solution, must not be administered in the following cases:

• hypersensitivity to levofloxacin or to other quinolones, or to any of the excipients of the medicinal product;
• epilepsy;
• history of tendon-related adverse reactions following prior use of quinolones;
• pediatric age (under 18 years);
• pregnancy and breastfeeding.

Special precautions.

For single use only. Discard any unused solution.

Before administration, the medicinal product should be visually inspected for the presence of particles and discoloration. Only clear greenish-yellow solution free from particulate matter should be used. Levocin-N, infusion solution, should be used immediately (within 3 hours) after perforation of the rubber stopper to prevent any bacterial contamination. No light protection is required during infusion.

This medicinal product may be administered separately or with the following solutions: 0.9% sodium chloride solution; 5% glucose solution; 2.5% Ringer's solution with glucose; combined solutions for parenteral nutrition (amino acids, carbohydrates, electrolytes).

Information on incompatibilities is provided in the section "Incompatibilities".

From a microbiological standpoint, the medicinal product should be used immediately after first opening. If not used immediately, the responsibility for storage conditions and duration during use lies with the user.

Any unused medicinal product or waste material must be disposed of in accordance with local requirements.

Interaction with other medicinal products and other types of interactions.

Effects of other medicinal products on levofloxacin.

Theophylline, fenbufen, or similar nonsteroidal anti-inflammatory drugs

No pharmacokinetic interaction between levofloxacin and theophylline was observed in clinical studies. However, a significant reduction in seizure threshold may occur when quinolones are used concomitantly with theophylline, nonsteroidal anti-inflammatory drugs, or other agents that lower the seizure threshold. Levofloxacin concentrations were approximately 13% higher in the presence of 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. This is because both drugs can block tubular secretion of levofloxacin. However, at the doses tested in studies, it is unlikely that statistically significant kinetic differences would have clinical relevance. Levofloxacin should be used with caution in combination with medicinal products affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other information

Clinical pharmacology studies have demonstrated that the following medicinal products do not have any clinically significant effect on the pharmacokinetics of levofloxacin: calcium carbonate, digoxin, glyburide (glibenclamide), ranitidine.

Effects 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 coagulation parameters (INR/prothrombin time) and/or bleeding events, which may be severe, have been reported. Therefore, patients receiving concomitant vitamin K antagonists should be monitored for coagulation parameters (see section "Special warnings and precautions for use").

Medicinal products that prolong the QT interval

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

Other significant 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 Warnings and Precautions for Use.

Levofloxacin should be avoided in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones. Treatment with levofloxacin in such patients should only be initiated if no alternative treatment options are available and after careful benefit-risk assessment.

Prolonged, disabling and potentially irreversible serious adverse reactions

Very rare cases of prolonged (lasting months or years), disabling and potentially irreversible serious adverse reactions affecting various, and sometimes multiple systems simultaneously (including musculoskeletal, nervous system, psychiatric and sensory organs) have been reported in patients receiving quinolones and fluoroquinolones, regardless of age or underlying risk factors. Administration of 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 recommended duration of infusion is at least 60 minutes for the 500 mg levofloxacin solution for infusion.

With ofloxacin, tachycardia and transient lowering of blood pressure have been observed during infusion. In rare cases, this may lead to a marked drop in blood pressure or circulatory collapse. If a significant decrease in blood pressure occurs during levofloxacin (l-isomer of ofloxacin) infusion, the infusion should be stopped immediately.

Pulmonary anthrax

Clinical experience is based on in vitro susceptibility studies of Bacillus anthracis, as well as animal experimental data and limited human data. Physicians should refer to established national and/or international guidelines for the treatment of anthrax.

Methicillin-resistant Staphylococcus aureus (MRSA)

Methicillin-resistant Staphylococcus aureus (MRSA) is very likely to exhibit cross-resistance to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of known or suspected MRSA infections unless laboratory testing confirms susceptibility to levofloxacin (see section "Pharmacodynamics").

Resistance of Escherichia coli, the most common cause of urinary tract infections, to fluoroquinolones varies across different countries of the European Union. When prescribing levofloxacin, physicians should consider local prevalence of fluoroquinolone resistance in Escherichia coli.

Tendinitis and tendon rupture

Tendinitis and tendon ruptures (not limited to the Achilles tendon), sometimes bilateral, may occur as early as 48 hours after initiation of quinolone or fluoroquinolone therapy and have been reported even several months after discontinuation of treatment in patients receiving a daily dose of 1000 mg levofloxacin. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, organ transplant recipients, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.

If signs of tendinitis (e.g., painful swelling, inflammation) occur, treatment with the drug should be discontinued and alternative therapy considered. The affected limb(s) 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 levofloxacillin dose 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, particularly severe, persistent and/or hemorrhagic diarrhea occurring during or after treatment with levofloxacin (sometimes weeks after treatment) may be a symptom of Clostridium difficile-associated disease (CDAD). The severity of CDAD ranges from mild to life-threatening. The most severe form is pseudomembranous colitis. This diagnosis should therefore be considered in patients who develop severe diarrhea during or after levofloxacin therapy. If pseudomembranous colitis is suspected, levofloxacin infusion should be stopped immediately and appropriate treatment initiated. Medicinal products that inhibit intestinal motility 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, as with other quinolones, should be used with extreme caution in patients predisposed to seizures, such as those with prior central nervous system disorders or those receiving concomitant medications that lower the cerebral seizure threshold (e.g., theophylline) (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"). If seizures occur, levofloxacin therapy should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or manifest glucose-6-phosphate dehydrogenase deficiency may be susceptible to hemolytic reactions during treatment with quinolone antibacterial agents; therefore, levofloxacin should be administered with caution in such patients, with close monitoring for hemolysis.

Patients with renal impairment

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

Hypersensitivity reactions

Levofloxacin may occasionally cause serious, potentially fatal hypersensitivity reactions (e.g., angioedema up to anaphylactic shock) after administration of the initial dose (see section "Adverse Reactions"). In such cases, patients should immediately discontinue treatment and seek medical advice or call emergency services for appropriate emergency measures.

Serious skin reactions

Serious dermatologic adverse reactions (SDRs), such as toxic epidermal necrolysis (TEN, also known as Lyell's syndrome), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with levofloxacin use, which may be life-threatening or fatal (see section "Adverse Reactions"). Patients should be informed about these manifestations and symptoms at the time of prescription, and closely monitored. If manifestations or symptoms related to these reactions occur, levofloxacin should be discontinued and alternative therapy considered. If patients develop serious adverse reactions such as SJS, TEN, or DRESS reaction, levofloxacin should be discontinued immediately and medical advice sought.

Initial signs of SJS/TEN include reddish target-like spots or roundish rashes with central blisters. Oral, pharyngeal, nasal, genital, and ocular lesions (red, swollen eyes) may also appear. These severe skin reactions are often preceded by fever and flu-like symptoms. Skin rashes may progress to extensive skin peeling, dangerous complications, or fatal outcomes.

Initial signs of DRESS syndrome include flu-like symptoms and facial rash, which then progress to widespread rash, high fever, elevated liver enzymes (detected in blood tests), increased white blood cell count (eosinophilia), and lymphadenopathy.

In case of severe rash or other symptoms listed above, levofloxacin should be discontinued immediately and medical advice sought.

Blood glucose fluctuations

As with other quinolones, fluctuations in blood glucose levels, including hyperglycemia and hypoglycemia, have been reported, particularly in diabetic patients receiving concomitant therapy with oral 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").

Phototoxicity prevention

Although phototoxicity is very rare with levofloxacin, patients are advised to avoid unnecessary exposure to strong sunlight or artificial UV radiation (e.g., UV lamps, sunbeds) during treatment and for 48 hours after discontinuation of treatment.

Patients receiving vitamin K antagonists

Due to the potential for increased coagulation test results (PT/INR) and/or bleeding in patients taking levofloxacin concomitantly with vitamin K antagonists (e.g., warfarin), coagulation tests should be monitored when these drugs are used together (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. In very rare cases, 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, levofloxacin should be discontinued and appropriate measures taken. Levofloxacin should be used with caution in patients with a history of psychiatric disorders or psychiatric illness.

QT interval prolongation

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

• congenital QT prolongation 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);
• elderly patients and women, who may have increased sensitivity to QT-prolonging drugs;
• cardiac disease (e.g., heart failure, myocardial infarction, bradycardia) (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction", "Dosage and Administration", "Overdose", "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. Patients should be advised to inform their physician immediately if they experience symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness to prevent progression to potentially irreversible conditions.

Opioids

Urine testing for opioids in patients receiving levofloxacin may yield false-positive results. Confirmation of positive opioid results using more specific methods may be necessary.

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 (e.g., sepsis) (see section "Adverse Reactions"). Patients should be advised to discontinue treatment and consult a physician if symptoms of liver disease such as anorexia, jaundice, dark urine, pruritus, or abdominal pain occur.

Exacerbation of myasthenia gravis

Fluoroquinolones, including levofloxacin, may cause neuromuscular blockade and exacerbate muscle weakness in patients with myasthenia gravis. Serious adverse reactions reported in the post-marketing period, including fatal cases and the need for 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 vision is impaired or any ocular effects occur, patients should seek immediate ophthalmologic consultation (see sections "Ability to Influence Reaction Speed When Driving or Operating Machinery" and "Adverse Reactions").

Superinfection

The use of levofloxacin, especially over prolonged periods, may lead to overgrowth of microorganisms not susceptible to the drug. If superinfection occurs during therapy, appropriate measures should be taken.

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

Aortic aneurysm and dissection, and cardiac valve regurgitation/insufficiency

Epidemiological studies have reported 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 cardiac valve regurgitation/insufficiency have been reported in patients receiving fluoroquinolones (see section "Adverse Reactions").

Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and consideration of alternative therapeutic options in patients with a positive family history of aneurysm or congenital heart valve defects, or in patients with existing diagnosis of aortic aneurysm and/or dissection, heart valve disease, or other risk factors or predisposing conditions:

• for both aortic aneurysm/dissection and cardiac valve regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, hypertension, rheumatoid arthritis); or additionally
• for aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, known atherosclerosis, or Sjögren's syndrome); or additionally
• for cardiac valve regurgitation/insufficiency (e.g., infective endocarditis). The risk of aortic aneurysm, dissection, and rupture may be increased in patients receiving systemic corticosteroids concomitantly.

Patients should seek immediate medical attention if they experience sudden abdominal, chest, or back pain.

Patients should be advised to seek immediate medical help if they develop acute dyspnea, new-onset palpitations, or swelling of the abdomen or lower limbs.

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 be evaluated by a physician immediately. If acute pancreatitis is suspected, levofloxacin should be discontinued; if confirmed, levofloxacin should not be restarted. Caution should be exercised 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 any of these disorders are suspected, blood test results should be monitored. If abnormal results are obtained, discontinuation of levofloxacin therapy should be considered.

Sodium.

This medicinal product contains 7.7 mmol (177.1 mg) of sodium in 50 ml of solution and 15.4 mmol (354.2 mg) of sodium in 100 ml of solution. This should be taken into account for patients on a sodium-restricted diet and in situations where water intake must be limited.

Use during pregnancy or breastfeeding.

Pregnancy.

The number of studies on the use of levofloxacin during pregnancy is limited. Animal studies do not indicate direct or indirect harmful effects on reproductive toxicity. However, due to the lack of human data and experimental evidence indicating a risk of fluoroquinolone-induced joint cartilage damage in the growing organism, levofloxacin should not be administered to pregnant women (see section "Contraindications").

Breastfeeding.

Levofloxacin is contraindicated in women who are breastfeeding. There is insufficient information on the excretion of levofloxacin in breast milk, although other fluoroquinolones are known to pass into breast milk. Due to the lack of human data and experimental evidence indicating a risk of fluoroquinolone-induced joint cartilage damage in the growing organism, levofloxacin should not be administered to women who are breastfeeding (see section "Contraindications").

Fertility.

Levofloxacin does not impair fertility or reproductive function in animals.

Ability to influence reaction speed when driving or operating machinery.

Some adverse effects (e.g., dizziness/vertigo, somnolence, visual disturbances) may impair a patient's ability to concentrate and react, and therefore may pose a risk in situations where such ability is particularly important (e.g., driving a car or operating machinery).

Method of administration and dosage.

Levocin-N, infusion solution, should be administered slowly by intravenous infusion once or twice daily. The dosage depends on the type and severity of the infection and the susceptibility of the likely causative organism. It is possible to switch from initial intravenous administration of levofloxacin to the appropriate oral dosage form according to the instructions for medical use of the drug in tablet form, depending on the patient's condition. Due to the bioequivalence of oral and parenteral forms, the dosage may be the same.

Table 3

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

1 The duration of treatment includes both intravenous and oral administration. The time to switch from intravenous to oral administration depends on the clinical condition, but usually takes from 2 to 4 days.

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

Table 4

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

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

Dosing in patients with hepatic impairment. Dose adjustment is not necessary, since levofloxacin is minimally metabolized in the liver and is primarily excreted by the kidneys.

Dosing in elderly patients. If renal function is not impaired, there is no need for
dose adjustment in elderly patients (see section "Special instructions").

The intravenous solution should be administered intravenously slowly by infusion once or twice daily. The infusion period for Levoxin-N should be no less than 60 minutes for the 500 mg dose (see also section "Special instructions***"***).

For information on incompatibility of Levoxin-N with other infusion solutions, see section "Incompatibility", and for compatibility, see section "Special precautions".

The duration of treatment depends on the course of the disease and should not exceed 14 days.

Children.

The drug is contraindicated in children (under 18 years of age) because of the potential risk of damage to articular cartilage.

Overdose.

Symptoms: dizziness, impaired or altered consciousness, seizures, tremor, QT interval prolongation, or exacerbation of other adverse reactions. CNS effects, including confusion, seizures, myoclonus, hallucinations, and tremor, have been observed in the post-marketing period. In case of overdose, careful patient monitoring including ECG should be performed.

Treatment − symptomatic. There are no specific antidotes. Hemodialysis, including peritoneal dialysis or CAPD, is not effective in removing levofloxacin from the body.

Adverse Reactions

The information below is based on data from clinical trials involving over 8300 patients and extensive post-marketing experience.

The frequencies in the table below are defined according to the following convention: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), and not known (cannot be estimated from available data).

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

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

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

*Very rare cases of prolonged (up to months or years), disabling and potentially irreversible serious adverse reactions affecting multiple, sometimes widespread, organ systems and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, difficulty walking; in some cases, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disturbances, and disturbances of hearing, vision, taste, and smell) have been associated with the use of quinolones and fluoroquinolones, regardless of pre-existing risk factors (see section "Special precautions for use"); anxiety, suicidal thoughts, panic attacks, neuralgia, and attention disorders have also been reported as potential aspects of prolonged and disabling adverse reactions caused by fluoroquinolones.

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

Other adverse reactions associated with administration of fluoroquinolones: porphyria attacks in patients with porphyria.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as patients' legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Shelf life after first opening of the vial

Levocin-N for infusion should be used immediately after perforation of the rubber stopper in the cap (within 3 hours) to prevent any bacterial contamination.

Any unused contents of the vial should be discarded and must not be stored for later use.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach of children. Do not freeze.

Incompatibilities.

Levocin-N infusion solution must not be mixed with heparin or alkaline solutions (e.g., sodium bicarbonate). For a list of solutions compatible with the medicinal product, see section "Special precautions for safety".

Packaging.

100 ml or 150 ml in a vial; 1 vial per pack or 10 vials per box.

Prescription status.

Prescription only.

Manufacturer.

VIOSEAL S.A. PARENTERAL SOLUTIONS INDUSTRY.

LLC "FARMASEL".

Manufacturer's address and place of business.

9th km National Road Trikala-Larissa, Taxiarchis Trikala, 42100, Greece.

Ukraine, 07408, Kyiv region, Brovary district, village Kvitneve, Prorizna Street, 3.