Levoximed

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

Composition:

Active substance: levofloxacin;

100 ml of solution contains levofloxacin (in the form of levofloxacin hemihydrate) 500 mg;

Excipients: sodium chloride, hydrochloric acid concentrated, 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. Levofloxacin. ATC code J01MA12.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial agent belonging to the fluoroquinolone group,

the S-enantiomer of the racemic mixture of ofloxacin.

Mechanism of action

Levofloxacin acts on the DNA-DNA gyrase complex and topoisomerase IV.

Pharmacokinetic/pharmacodynamic relationship

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

Mechanism of resistance

Resistance to levofloxacin develops through stepwise mutations in the target site of both types of type II topoisomerases, 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 is observed between levofloxacin and other fluoroquinolones. Due to its mechanism of action, there is no cross-resistance between levofloxacin and other classes of antibacterial agents.

Breakpoints

The breakpoints for minimum inhibitory concentration (MIC) of levofloxacin recommended by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which distinguish susceptible microorganisms from those with intermediate susceptibility (moderately resistant) and intermediate-susceptible from resistant organisms, are presented in the MIC testing table below.

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

1 Only uncomplicated urinary tract infections.

2 Susceptibility conclusion can be drawn based on susceptibility to ciprofloxacin.

Resistance prevalence may vary geographically and over time for individual species, and it is advisable to obtain local information on resistance, especially when treating severe infections. If necessary, expert advice 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-susceptible, 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.

Variable susceptibility (acquired resistance >10 %)

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.

Distribution

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

Penetration into tissues and body fluids

Levofloxacin has been shown to penetrate bronchial mucosa, bronchoalveolar fluid, alveolar macrophages, lung tissue, skin (blister fluid), prostate tissue, and urine. Penetration into cerebrospinal fluid is poor.

Metabolism

Levofloxacin undergoes minimal metabolism, with metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the administered compound 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). 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 after intravenous and oral administration, indicating that these routes (oral and intravenous) are interchangeable.

There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration.

Linearity

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

Special populations.

Patients with renal impairment

Renal impairment affects the pharmacokinetics of levofloxacin. With decreased renal function, renal elimination and clearance are reduced, and elimination half-life is prolonged, as shown in the table below.

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

Elderly patients

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

Gender differences

Separate analysis for 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.

Treatment of the following infectious diseases (see sections "Special precautions" and "Pharmacological properties" (Pharmacodynamics)) in adults:

• Acute pyelonephritis and 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").

For the following infectious diseases, levofloxacin should be used only when other antibacterial medicinal products, primarily indicated for initial treatment of these infections, are insufficiently effective:

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

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

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Theophylline, fenbufen, or similar nonsteroidal anti-inflammatory drugs

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, nonsteroidal anti-inflammatory drugs, or other agents that lower the seizure threshold. Levofloxacin concentrations were approximately 13% higher in the presence of fenbufen compared to levofloxacin 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 agents 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. Concomitant use of levofloxacin with medicinal products affecting tubular secretion, such as probenecid and cimetidine, should be done with caution, especially in patients with renal impairment.

Other information

Pharmacological clinical studies have demonstrated that the pharmacokinetics of levofloxacin were not clinically significantly affected when levofloxacin was administered concomitantly with the following medicinal products: calcium carbonate, digoxin, glyburide, ranitidine.

Cyclosporine

When administered concomitantly with levofloxacin, the elimination half-life of cyclosporine increases by 33%.

Vitamin K antagonists

When levofloxacin is used concomitantly with vitamin K antagonists (e.g., warfarin), increases in coagulation parameters (INR/international normalized ratio) and/or bleeding events, which may be severe, have been reported. Therefore, when these agents are used 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 antipsychotics) (see section "Special precautions" (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 precautions for use.

The use of the medicinal product should be avoided in patients with a history of serious adverse reactions to quinolone- or fluoroquinolone-containing products (see section "Adverse Reactions"). Treatment of such patients should be initiated only if no alternative therapy is available and after careful benefit-risk assessment (also see section "Contraindications").

Duration of infusion

The recommended duration of infusion is at least 30 minutes for a 250 mg dose or 60 minutes for a 500 mg dose. With ofloxacin, tachycardia and transient increases in blood pressure have been observed during infusions. In rare cases, this may lead to a sudden drop in blood pressure or circulatory collapse. If a marked decrease in blood pressure occurs during levofloxacin (*l-*isomer of ofloxacin) infusion, the infusion should be stopped immediately.

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

Methicillin-resistant Staphylococcus aureus 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, except when laboratory testing confirms susceptibility of the pathogen to levofloxacin.

Use in infections caused by E. coli

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

Use in pulmonary anthrax

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

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

Rarely, prolonged (months or years), disabling, and potentially irreversible serious adverse reactions affecting multiple organ systems (musculoskeletal, nervous system, psychiatric, and sensory organs), sometimes involving several systems simultaneously, have been reported with quinolone and fluoroquinolone use, regardless of age or presence of risk factors. If early symptoms or signs of any serious adverse reaction occur, the medicinal product should be discontinued immediately and medical advice sought.

Risk of tendinitis and tendon rupture

Tendinitis, most commonly affecting the Achilles tendon and potentially leading to tendon rupture, may rarely occur during levofloxacin therapy. Tendonitis and tendon ruptures, sometimes bilateral, may occur within 48 hours of starting levofloxacin or even several months after discontinuation. Patients at higher risk include those over 60 years of age, those receiving a daily dose of 1000 mg levofloxacin, and those taking corticosteroids. Patients who have undergone organ transplantation are at increased risk of tendinitis; therefore, the medicinal product should be used with caution in this population. The daily dose should be adjusted in elderly patients based on creatinine clearance (see section "Dosage and administration"). Elderly patients should be monitored during treatment. If symptoms of tendinitis develop, medical advice should be sought. If tendinitis is suspected, the medicinal product should be discontinued immediately and appropriate treatment initiated (e.g., immobilization of the affected tendon).

Risk of 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.

Risk of Clostridium difficile-associated disease

Diarrhea, particularly severe, persistent, and/or hemorrhagic, during or after levofloxacin therapy (including several weeks after treatment) may be a symptom of Clostridium difficile-associated disease (CDAD), the most severe form of which is pseudomembranous colitis (see section "Special precautions for use"). The severity of CDAD ranges from mild to life-threatening. This diagnosis should be considered in patients who develop severe diarrhea during or after levofloxacin therapy. If pseudomembranous colitis is suspected, the medicinal product should be discontinued immediately and appropriate treatment initiated promptly. Antiperistaltic agents are contraindicated in this clinical situation.

Use in patients predisposed to seizures

Quinolones may lower the seizure threshold and provoke seizures. The medicinal product is contraindicated in patients with a history of epilepsy (see section "Contraindications") and, as with 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"), the medicinal product should be discontinued.

Use in 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-class antibacterial agents; therefore, the medicinal product should be used with caution in such patients, and monitoring for hemolysis should be performed.

Use in patients with renal impairment

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

Risk of 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"). If such reactions occur, the medicinal product should be discontinued immediately and medical advice sought.

Risk of severe skin reactions

Severe skin 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 and may be life-threatening or fatal (see section "Adverse Reactions"). Patients should be informed of possible signs and symptoms of severe skin reactions and monitored closely. If signs or symptoms suggestive of such reactions occur, the medicinal product should be discontinued immediately and alternative therapy considered. If a patient develops severe skin reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, or DRESS syndrome during levofloxacin therapy, levofloxacin treatment must never be repeated at any time.

Risk of dysglycemia

Alterations in plasma glucose levels, including hypoglycemia and hyperglycemia, have been reported with levofloxacin use. Dysglycemia occurred predominantly in elderly patients with diabetes receiving concomitant therapy with oral hypoglycemic agents (e.g., sulfonylureas) or insulin. Cases of hypoglycemic coma have been reported. When used 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 discontinued immediately and alternative antibacterial therapy with non-fluoroquinolone agents considered.

Prevention of photosensitization

Although photosensitization is very rare with levofloxacin (see section "Adverse Reactions"), to avoid it, 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.

Use in patients taking vitamin K antagonists

Due to possible increases in coagulation test parameters (PT/INR) and/or bleeding in patients receiving levofloxacin concomitantly with vitamin K antagonists (e.g., warfarin), coagulation tests should be monitored when these agents are used together (see section "Interaction with other medicinal products and other forms of interaction").

Risk of psychiatric reactions

Psychiatric reactions have been reported with 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, the medicinal product should be discontinued and appropriate measures taken. The medicinal product should be used with caution in patients with psychiatric disorders or a history of psychiatric illness.

Aortic aneurysm/dissection and cardiac valve regurgitation/insufficiency

Epidemiological studies have reported an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and regurgitation of aortic and mitral valves 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 be used only after careful benefit-risk assessment and consideration of alternative therapeutic options in patients with a positive family history of aneurysm or congenital heart valve defect, or in patients with existing diagnosis of aneurysm and/or aortic dissection, or heart valve disease, or in the presence of 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/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.

If sudden abdominal, chest, or back pain occurs, patients should seek immediate medical attention at an emergency department.

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

Risk of QT interval prolongation

The medicinal product 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, antipsychotics);
• uncorrected electrolyte imbalances (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 section "Dosage and administration" (Elderly patients); section "Interaction with other medicinal products and other forms of interaction", "Adverse Reactions", "Overdose").

Risk of peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy, leading to paresthesia, hypoesthesia, dysesthesia, or weakness, have been reported with quinolone and fluoroquinolone use. If symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur, medical advice should be sought to prevent progression to potentially irreversible conditions (see section "Adverse Reactions").

Risk of hepatobiliary disorders

Cases of necrotizing 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"). If signs or symptoms of liver disease occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain, the medicinal product should be discontinued and medical advice sought.

Exacerbation of myasthenia gravis

Fluoroquinolones, including levofloxacin, block neuromuscular transmission and may provoke muscle weakness in patients with myasthenia gravis. Serious adverse reactions, including fatalities and need for respiratory support, have been reported post-marketing in patients with myasthenia gravis receiving fluoroquinolones. The medicinal product is not recommended for use in patients with a history of myasthenia gravis.

Risk of visual disturbances

If visual disturbances or other ocular effects occur during treatment, immediate consultation with an ophthalmologist is required (see sections "Ability to influence driving and use of machines" and "Adverse Reactions").

Risk of superinfection

The use of levofloxacin, particularly for prolonged periods, may lead to overgrowth of microorganisms not susceptible to the medicinal product. If superinfection develops during treatment, appropriate measures should be taken.

Effect on laboratory tests

In patients receiving levofloxacin, urine opiate screening may yield false-positive results. Confirmation of positive opiate test results using more specific methods may be necessary. Levofloxacin inhibits the growth of Mycobacterium tuberculosis, potentially leading to false-negative bacteriological test results in patients with tuberculosis.

Risk of acute pancreatitis

Acute pancreatitis may occur in patients receiving 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 immediately. If acute pancreatitis is suspected, the medicinal product should be discontinued. Re-administration is not permitted if the diagnosis is confirmed. The medicinal product should be used with caution in patients with a history of pancreatitis (see section "Adverse Reactions").

Blood disorders

Bone marrow suppression, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, or agranulocytosis, may develop during levofloxacin therapy (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.

Information on excipients

The medicinal product contains 15.4 mmol (354 mg) of sodium per 100 ml of solution. This should be taken into account for patients on a sodium-controlled diet.

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 harmful effects on reproductive toxicity. Due to the lack of human studies and the potential for quinolones to damage developing joint cartilage, the medicinal product is contraindicated during pregnancy (see section "Contraindications"). If pregnancy is diagnosed during treatment, the physician should be informed.

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 developing joint cartilage, the medicinal product is contraindicated during breastfeeding (see section "Contraindications").

Fertility

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

Ability to influence driving and use of machines

Levofloxacin 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 concentration and reaction speed and thus increase the risk in situations where these abilities are particularly important (e.g., driving a car or operating machinery).

Method of administration and dosage.

The medicinal product is intended for intravenous use.

Prior to administration of the medicinal product, a sensitivity test must be performed.

Dosage

The dosage depends on the type and severity of infection, as well as on the susceptibility of the likely pathogen to levofloxacin.

Patients may be switched from initial intravenous administration of levofloxacin to appropriate oral administration according to the instructions for medical use of the medicinal product in tablet form, depending on the patient's condition. Due to the bioequivalence of oral and parenteral forms, the dosage may remain the same.

Dosage for patients with normal renal function (creatinine clearance exceeding 50 ml/min)

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

Dosing for patients with impaired renal function (creatinine clearance less than 50 ml/min)

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

Dosing in patients with hepatic impairment

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

Dosing in elderly patients

If renal function is not impaired, dose adjustment is not required in these patients (see section "Special precautions": (Risk of tendinitis and tendon rupture. Risk of QT interval prolongation)).

Method of administration

The medicinal product should be administered as a slow intravenous infusion. The solution should be infused once or twice daily. The infusion time should be at least 30 minutes for the 250 mg dose or 60 minutes for the 500 mg dose (see section "Special precautions").

Mixing with other infusion solutions

Levofloxacin infusion solution should not be mixed with heparin or alkaline solutions (e.g., sodium bicarbonate). The infusion solution is compatible with the following infusion solutions: 0.9% sodium chloride solution, 5% dextrose solution, 2.5% dextrose in Ringer's solution, and multi-component parenteral nutrition solutions (amino acids, carbohydrates, electrolytes). It should not be mixed with other solutions except those listed above.

Children.

The use of this medicinal product is contraindicated in children (under 18 years of age).

Overdose.

Symptoms

The most significant expected symptoms of levofloxacin overdose involve the CNS (dizziness, disturbances of consciousness, and seizures). According to study results, administration of doses higher than therapeutic ones has been associated with QT interval prolongation. During post-marketing studies, the following CNS adverse effects have been observed: confusion, convulsions, myoclonus, hallucinations, and tremor.

Treatment

In case of overdose, symptomatic therapy should be administered according to clinical manifestations. In cases of overdose, careful patient monitoring, including ECG, is required. Hemodialysis, including peritoneal dialysis or CAPD, is not effective in removing levofloxacin from the body. There are no specific antidotes.

Adverse Reactions

The information below is based on data from clinical trials and post-marketing experience.

Frequency is defined according to the following conventional categories: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

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

Infections and infestations:

Uncommon – fungal infections, including Candida species; resistance of pathogenic microorganisms.

Blood and lymphatic system disorders:

Uncommon – leukopenia, eosinophilia; rare – thrombocytopenia, neutropenia; not known – bone marrow suppression, including aplastic anemia, pancytopenia, agranulocytosis, hemolytic anemia.

Immune system disorders:

Rare – hypersensitivity reactions, including angioedema (see section "Special precautions"); frequency not known – anaphylactic/anaphylactoid shock** (see section "Special precautions").

Endocrine system disorders:

Frequency not known – syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders:

Uncommon – anorexia; rare – hypoglycemia, mainly in diabetic patients (see section "Special precautions"); frequency not known – hyperglycemia; hypoglycemic coma (see section "Special precautions").

Psychiatric disorders*:

Common – insomnia; uncommon – anxiety, confusion, restlessness; rare – psychotic reactions (including hallucinations, paranoia), depression, agitation, uneasiness, unusual dreams, nightmares, delirium; frequency not known – psychotic reactions with self-destructive behavior, including suicidal ideation or actions (see section "Special precautions"), mania.

Nervous system disorders*:

Common – headache, dizziness; uncommon – somnolence, tremor, dysgeusia (subjective taste disturbance); rare – seizures (see section "Contraindications" and "Special precautions"), paresthesia, memory impairment; frequency not known – peripheral sensory or sensorimotor neuropathy (see "Special precautions"), olfactory disturbances (parosmia), including anosmia (loss of smell), dyskinesia (movement coordination disorder), extrapyramidal disorders, ageusia (loss of taste), syncope (fainting), benign intracranial hypertension, myoclonus.

Eye disorders*:

Rare – visual disturbances such as blurred vision (see "Special precautions"); frequency not known – transient loss of vision (see "Special precautions"), 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 that may lead to cardiac arrest, ventricular arrhythmia of the torsade de pointes type (mainly in patients with risk factors for QT interval prolongation), QT interval prolongation on electrocardiogram (see sections "Special precautions": QT interval prolongation, and "Overdose").

Vascular disorders****:

Common – phlebitis (applies to injectable forms); rare – arterial hypotension.

Respiratory system 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 precautions"), pancreatitis (see section "Special precautions").

Hepatobiliary disorders:

Common – increased liver enzyme levels (ALT/AST, alkaline phosphatase, GGT); uncommon – increased plasma bilirubin levels; frequency not known – jaundice and severe hepatic injury, including cases of acute liver failure (sometimes fatal), mainly in patients with severe underlying diseases (see section "Special precautions"), hepatitis.

Skin and subcutaneous tissue disorders***:

Uncommon – rash, pruritus, urticaria, hyperhidrosis; rare – drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), fixed drug eruption; frequency not known – toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, erythema multiforme, photosensitivity reactions (see "Special precautions"), leukocytoclastic vasculitis, stomatitis, skin hyperpigmentation.

Musculoskeletal and connective tissue disorders*:

Uncommon – arthralgia, myalgia; rare – tendon disorders (see section "Special precautions"), including tendon inflammation (tendinitis) (e.g., Achilles tendon), muscle weakness, which may be particularly significant in patients with myasthenia gravis (see section "Special precautions"); frequency not known – muscle disorders (rhabdomyolysis), tendon rupture (e.g., Achilles tendon: see section "Special precautions"), ligament rupture, muscle rupture, arthritis.

Renal and urinary disorders:

Uncommon – increased plasma creatinine levels; rare – acute renal failure (e.g., due to interstitial nephritis).

General disorders and administration site conditions*:

Common – infusion site reactions (pain, redness); uncommon – asthenia; rare – pyrexia; frequency not known – pain (including back, chest, and limb pain).

* In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of existing risk factors, have reported long-term (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting various, and sometimes multiple simultaneously, organ systems and sensory organs (including reactions such as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, anxiety, suicidal thoughts, panic attacks, neuralgia, concentration difficulties, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disturbances, hearing, vision, taste, and smell disturbances) (see section "Special precautions").

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

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

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

Other adverse effects associated with the use of fluoroquinolones include:

• Extrapyramidal symptoms and other movement coordination disorders;
• Hypersensitivity vasculitis;
• Acute attacks of porphyria in patients with known porphyria.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after the medicine has been authorized is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals are encouraged to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25°C in the original packaging and in a place inaccessible to children.

Incompatibilities.

Levofloxacin infusion solution must not be mixed with heparin or alkaline solutions (e.g., sodium bicarbonate).

Packaging.

100 ml in vials, 1 vial in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLД MEDICINE ILAC SAN. VE TIC. A.S., Turkey /
WORLD MEDICINE ILAC SAN. VE TIC. A.S., Turkey.

Manufacturer's address and location of business operations.

COSB G.O.Pasa Mah. 6. Cad. No:30, Cerkezkoy/Tekirdag, Turkey.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine.