Eurolox

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT EUROFLOX (EUROFLOX)

Composition:

Active ingredient: levofloxacin;

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

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

Pharmaceutical form. Infusion solution.

Main physico-chemical properties: clear solution, yellow to greenish-yellow in color.

Pharmacotherapeutic group

Antibacterial agents of the quinolone group. Fluoroquinolones. ATC code J01MA12.

Pharmacological Properties

Pharmacodynamics

Levofloxacin is a synthetic antibacterial agent from the group of fluoroquinolones,

the S(-) enantiomer of the racemic mixture of the drug ofloxacin.

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

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 concentration-time curve (AUC) to the minimum inhibitory (suppressive) concentration (MIC).

Mechanism of resistance. The primary mechanism of resistance results from mutations in the target site of type II topoisomerases, DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as permeability barriers (typical for Pseudomonas aeruginosa) and efflux mechanisms, may also affect susceptibility to levofloxacin. Cross-resistance among levofloxacin and other fluoroquinolones is commonly observed. Due to its mechanism of action, cross-resistance between levofloxacin and other classes of antibacterial agents is generally not expected.

Clinical breakpoints. The recommended breakpoints for levofloxacin MIC values established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which differentiate susceptible microorganisms from those with intermediate susceptibility and resistant microorganisms, are presented in the table below for MIC testing (mg/l).

Table 1

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

1 Only uncomplicated urinary tract infections.

2 Susceptibility depends on sensitivity to ciprofloxacin.

The prevalence of resistance may vary geographically and over time for individual species. Local information on resistance is desirable, especially when treating severe infections. Advice from a specialist should be sought when local resistance prevalence is such that the benefit of the drug, at least for certain types of infections, is questionable.

Typically susceptible species

Aerobic Gram-positive bacteria

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

Aerobic Gram-negative bacteria

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

Anaerobic bacteria

Peptostreptococcus.

Others

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

Species with potential for developing resistance

Aerobic Gram-positive bacteria

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

Aerobic Gram-negative bacteria

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

Anaerobic bacteria

Bacteroides fragilis.

Naturally resistant strains

Aerobic Gram-positive bacteria

Enterococcus faecium.

* Methicillin-resistant Staphylococcus aureus is likely to be cross-resistant to fluoroquinolones, including levofloxacin.

Pharmacokinetics

Absorption

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

Food has almost no 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 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, epithelial lining fluid, alveolar macrophages, lung tissue, skin (vesicle fluid), prostate tissue, and urine. However, levofloxacin penetrates poorly into cerebrospinal fluid.

Biotransformation

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

Elimination

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

Linearity

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

Special patient populations

Patients with renal impairment

Impaired renal function affects the pharmacokinetics of levofloxacin. With reduced renal function, renal excretion and clearance decrease, and elimination half-life increases (see Table 2).

Table 2

Pharmacokinetics in renal impairment after a single 500 mg oral dose

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 the pharmacokinetics of levofloxacin depending on gender. There is no evidence that these gender differences are clinically significant.

Clinical characteristics

Indications

Infections caused by microorganisms sensitive to the drug:

• 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 infections, levofloxacin should be used only when the use of other antibacterial agents, which are usually recommended for initial treatment of these infections, is inappropriate or impossible.

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

Contraindications

• Hypersensitivity to levofloxacin, other fluoroquinolones, or to any other component of the drug;
• Epilepsy;
• Tendon damage associated with previous use of fluoroquinolones;
• Pregnancy or breastfeeding;
• Pediatric age (under 18 years).

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 significant reduction in seizure threshold may occur with concomitant administration of quinolones and theophylline, NSAIDs, and other substances that reduce seizure threshold. The concentration of levofloxacin is approximately 13% higher when administered with fenbufen than when levofloxacin is taken alone.

Probenecid and cimetidine

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

Other information

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

Effect of levofloxacin on other medicinal products

Cyclosporine

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

Vitamin K antagonists

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

Other significant information

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

Concomitant use of levofloxacin with alcohol is not recommended.

Special precautions for use

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

Aortic aneurysm, aortic dissection and valvular regurgitation/insufficiency

Epidemiological studies have reported an increased risk of aortic aneurysm and dissection, particularly in elderly patients, as well as 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 assessment of benefit-risk ratio and consideration of alternative therapeutic options in patients with a family history of aneurysm or congenital heart valve defects, in patients with a confirmed diagnosis of aneurysm and/or aortic dissection or with heart valve disease, as well as in patients with other risk factors, such as:

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

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

In case of sudden abdominal, chest or back pain, patients should seek immediate medical attention at an emergency department.

Patients should be advised to seek immediate medical help if they experience acute shortness of breath, new onset palpitations, or development of abdominal or lower limb edema.

Resistance risks

Methicillin-resistant Staphylococcus aureus (MRSA) is often also resistant to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for treatment of infections where MRSA is known or suspected to be the causative pathogen, except when laboratory testing has confirmed susceptibility of the pathogen to levofloxacin.

Resistance to fluoroquinolones in Escherichia coli (the most common cause of urinary tract infections) varies across countries. When prescribing fluoroquinolones, local prevalence of fluoroquinolone resistance in E. coli should be taken into account.

Pulmonary anthrax

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

Infusion duration

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 may occur during levofloxacin infusion. Rarely, severe hypotension may lead to cardiovascular failure. If a significant drop in blood pressure occurs during levofloxacin (L-isomer of ofloxacin) infusion, the drug should be discontinued immediately.

Tendinitis and tendon rupture

Tendinitis may occur in individual patients. Development of tendinitis and tendon rupture (particularly, but not limited to, Achilles tendon), sometimes bilateral, may occur within the first 48 hours of initiating quinolone or fluoroquinolone therapy, and such cases have also been reported several months after discontinuation of the drug. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with impaired renal function, patients who have undergone solid organ transplantation, patients receiving a daily dose of 1000 mg levofloxacin, 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), levofloxacin therapy should be discontinued immediately and alternative treatment options considered. Affected limbs should be appropriately managed (e.g., immobilization). Corticosteroids are not recommended in cases of tendonopathy.

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. Levofloxacin should be discontinued immediately at the first sign of myoclonus, and appropriate treatment initiated.

Clostridium difficile-associated disease

Diarrhea, especially severe, persistent or with blood, during or after treatment (including several weeks after treatment) with levofloxacin may be a symptom of Clostridium difficile-associated disease (CDAD), which may range in severity from mild to life-threatening. The most severe form is pseudomembranous colitis. If pseudomembranous colitis is suspected, levofloxacin should be discontinued immediately and symptomatic and specific treatment initiated promptly (e.g., vancomycin). In such cases, drugs that inhibit intestinal motility are contraindicated.

Patients with seizure predisposition

Quinolones may lower the seizure threshold and provoke seizures. Levofloxacin is contraindicated in patients with a history of epilepsy (see section "Contraindications"). As with other quinolones, it should be used with extreme caution in patients predisposed to seizures, such as those with pre-existing central nervous system disorders, concomitant therapy with fenbufen or similar non-steroidal anti-inflammatory drugs, or drugs that increase seizure susceptibility (lower seizure threshold), such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). In case of seizure occurrence (see section "Adverse reactions"), levofloxacin should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or overt glucose-6-phosphate dehydrogenase deficiency may be prone to hemolytic reactions when treated with quinolone antibiotics. Therefore, if levofloxacin must be used in such patients, monitoring for possible hemolysis is required.

Patients with renal impairment

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

Hypersensitivity reactions

Levofloxacin may cause serious, potentially fatal hypersensitivity reactions (ranging from angioneurotic edema to anaphylactic shock), sometimes after the first dose (see section "Adverse reactions"). In case of hypersensitivity reactions, levofloxacin should be discontinued immediately, medical advice sought, and appropriate treatment initiated.

Severe skin adverse reactions

Severe skin adverse reactions have been reported with levofloxacin use, including toxic epidermal necrolysis (TEN, also known as Lyell's syndrome), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP), which may be life-threatening or fatal (see section "Adverse reactions").

Patients should be informed about signs and symptoms of severe skin reactions that may occur after drug administration and closely monitored. If signs and symptoms suggestive of these reactions appear, levofloxacin should be discontinued immediately and alternative treatment considered.

If a patient develops a serious reaction such as toxic epidermal necrolysis, Stevens-Johnson syndrome, DRESS syndrome, or AGEP after levofloxacin use, levofloxacin should never be prescribed to this patient again.

Disglycemia

As with other quinolones, cases of altered blood glucose levels, including both hypoglycemia and hyperglycemia, have been reported, usually in diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. In diabetic patients, careful monitoring of blood glucose levels is recommended (see section "Adverse reactions"). If a patient reports abnormal blood glucose levels, treatment should be discontinued immediately and alternative antibacterial therapy with non-fluoroquinolone agents considered.

Phototoxicity prevention

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

Patients receiving vitamin K antagonists

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

Psychotic reactions

Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. Very rarely, these progressed to suicidal thoughts and self-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. Caution is recommended when prescribing levofloxacin to patients with psychotic disorders or a history of psychiatric illness.

QT interval prolongation

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

• congenital or acquired long QT syndrome;
• concomitant use of medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics);
• electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
• cardiac disease (e.g., heart failure, myocardial infarction, bradycardia) (see sections "Interaction with other medicinal products and other forms of interaction", "Method of administration and dosage (Elderly patients)", "Overdose", "Adverse reactions");
• elderly patients and younger women may be more sensitive to QT-prolonging drugs; therefore, fluoroquinolones, including levofloxacin, should be used with caution in these patient groups.

Peripheral neuropathy

Cases of sensory or sensorimotor peripheral neuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving fluoroquinolones, including levofloxacin. Levofloxacin should be discontinued if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur to prevent irreversible damage.

Hepatobiliary disorders

Cases of necrotizing hepatitis progressing to fatal hepatic 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.

Acute pancreatitis

Acute pancreatitis may occur in patients taking levofloxacin. Patients should be informed about the characteristic symptoms of acute pancreatitis. Patients who develop nausea, malaise, abdominal discomfort, severe abdominal pain, or vomiting should be examined immediately by a physician. If acute pancreatitis is suspected, levofloxacin should be discontinued, and if confirmed, treatment with levofloxacin should not be resumed. Caution is advised when treating patients with a history of pancreatitis (see section "Adverse reactions").

Blood system disorders

Bone marrow suppression, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, or agranulocytosis, may occur during levofloxacin therapy (see section "Adverse reactions").

If any of these blood disorders are suspected, blood parameters should be monitored. If abnormalities are detected, discontinuation of levofloxacin therapy should be considered.

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 reported long-term (lasting months or years), disabling and potentially irreversible adverse reactions affecting various systems, sometimes multiple systems simultaneously (e.g., musculoskeletal, nervous, psychiatric, and sensory organs). The drug should be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and medical consultation sought.

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 associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances

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

Superinfection

The use of levofloxacin, especially prolonged use, may lead to overgrowth of microorganisms not susceptible (resistant) to the drug. If superinfection develops during therapy, appropriate measures should be taken.

Effect on laboratory test results

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

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

Excipients

This medicinal product contains 15.4 mmol (355 mg) of sodium per 100 ml of solution; therefore, caution should be exercised when administering it to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of levofloxacin in pregnant women are limited.

Due to the lack of human studies and the potential for quinolones to damage the articular cartilage in the growing organism, levofloxacin is contraindicated in pregnancy and in women who are breastfeeding. If pregnancy occurs during treatment, the physician should be informed.

Breastfeeding

Levofloxacin is contraindicated during breastfeeding. Information on the passage of levofloxacin into breast milk is insufficient, although 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, levofloxacin should not be administered to women who are breastfeeding.

Fertility

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

Ability to affect reaction speed when driving or operating machinery

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

Method of Administration and Dosage

Levofloxacin, solution for infusion, 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 pathogen. It is possible to switch from initial intravenous administration of levofloxacin to appropriate oral administration of the medicinal product in the form of film-coated tablets, according to the instructions for medical use, depending on the patient's condition. Considering the bioequivalence of oral and parenteral forms, equivalent dosing is possible.

Method of Administration

The following dosages are recommended for administration of levofloxacin:

Table 3

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

1The 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.

Table 4

Dosage for adult patients with impaired renal function in whom creatinine clearance < 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 required, 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, dose adjustment is not necessary (see section "Special precautions". Tendinitis and tendon rupture. QT interval prolongation).

Method of administration

Levofloxacin, solution for infusion, is intended only for slow intravenous infusion. The solution should be administered 1–2 times daily. The infusion time for levofloxacin should be at least 30 minutes for the 250 mg dose or 60 minutes for the 500 mg dose (see section "Special precautions***"***).

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

The solution should be inspected visually before use. Only clear solutions free from particles should be used.

Any unused medicinal product should be disposed of in accordance with current requirements.

Mixing with other infusion solutions

The medicinal product is compatible with the following infusion solutions:

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

For incompatibilities, see section "Incompatibilities".

Children

Levofloxacin is contraindicated in children and adolescents.

Overdose

According to toxicity studies in animals or clinical and pharmacological studies conducted with doses higher than therapeutic, the most serious signs expected after acute overdose of levofloxacin, solution for infusion, are CNS-related symptoms such as confusion, dizziness, altered consciousness, seizures, and QT interval prolongation.

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

Treatment. In cases of overdose, symptomatic treatment should be administered. ECG monitoring is required due to the potential for QT interval prolongation. Hemodialysis, including peritoneal dialysis and continuous ambulatory peritoneal dialysis (CAPD), is not effective in removing levofloxacin from the body. There are no specific antidotes.

Adverse reactions

The adverse reactions listed below are classified by organ systems and frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), frequency not known (frequency cannot be estimated based on available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Table 5

1 Anaphylactic and anaphylactoid reactions may sometimes occur even after administration of the first dose of the medicinal product.

2 Mucous membrane reactions may sometimes occur even after administration of the first dose of the medicinal product.

* In very rare cases, in patients receiving quinolones and fluoroquinolones, regardless of the presence of risk factors, there have been reports of long-term (lasting for months or years), disabling and potentially irreversible serious adverse reactions affecting various systems of the body and sensory organs, sometimes involving multiple systems simultaneously (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disturbances, hearing, vision, taste and smell disturbances) (see section "Special precautions for use"); there have also been reports of anxiety, suicidal thoughts, panic attacks, neuralgia and attention disturbances as potential aspects of long-term and disabling adverse reactions caused by fluoroquinolones.

** In patients receiving fluoroquinolones, cases of aneurysms and dissections of the aorta, sometimes complicated by rupture (including fatal cases), and regurgitation / insufficiency of any of the heart valves have been reported (see section "Special precautions for use").

Other adverse effects associated with fluoroquinolone use:

• Porphyria attacks in patients with existing porphyria.

Reporting of suspected adverse reactions

Reporting of adverse reactions after medicinal product registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions

Store at a temperature not exceeding 25 °C in the original packaging, protected from light. Do not freeze.

Keep out of reach of children.

Incompatibility

The medicinal product should not be mixed with infusion solutions and injections that have physical and chemical instability at pH 3–4 (such as sodium bicarbonate, penicillin, heparin).

The medicinal product should not be mixed with other medicinal products in the same container, except as specified in the section "Dosage and method of administration".

Packaging

100 ml in a polyvinyl chloride container, 1 container in a polymer film within a cardboard pack.

Prescription status. Prescription only.

Manufacturer

Subsidiary enterprise "Farmatreyd".

Manufacturer's location and address of business operations

85 Sambirska Street, Drohobych, Lviv Oblast, Ukraine.