Levoflor

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

Composition:

Active substance: levofloxacin;

1 ml of solution contains levofloxacin hemihydrate equivalent to 5 mg of levofloxacin;
Excipients: sodium chloride, hydrochloric acid, sodium hydroxide, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical characteristics: Clear, greenish-yellow solution, practically free from particles.

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. As a fluoroquinolone antibacterial agent, levofloxacin acts on the DNA complex with DNA gyrase and topoisomerase IV. The primary mechanism of resistance results from mutations in the gyr-A genes.

Breakpoints. In vitro, cross-resistance exists between levofloxacin and other fluoroquinolones. The recommended breakpoints for minimum inhibitory concentration (MIC) of levofloxacin established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which differentiate susceptible microorganisms from intermediate-susceptible (moderately resistant) organisms, and intermediate-susceptible from resistant organisms, are presented in Table 1 for MIC testing (mg/L). EUCAST clinical MIC breakpoints for levofloxacin:

Table 1

1 The breakpoints for levofloxacin refer to high-dose therapy.

2 Low-level resistance to fluoroquinolones may occur (MIC for ciprofloxacin 0.12–0.5 mg/L), but there is no evidence that such resistance has clinical significance in respiratory tract infections caused by H. influenzae.

3 Isolates with MIC values above the breakpoint between susceptible and intermediate (moderately resistant) strains are very rare or have not yet been reported. Susceptibility testing for identification and antimicrobial sensitivity on any such isolate should be repeated, and if confirmed, the isolate should be sent to an authorized laboratory. Until data demonstrating clinical response for confirmed isolates with MIC above the current resistant breakpoint become available, such isolates must be reported as resistant.

4 Breakpoints for oral doses ranging from a single 500 mg dose to 500 mg twice daily, and intravenous doses ranging from a single 500 mg dose to 500 mg twice daily.

Antibacterial spectrum.

The prevalence of resistance among selected species may vary geographically and over time. Local information on resistance patterns is desirable, especially when treating severe infections.

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:

Burkholderia cepacia**, 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 a problem:

Aerobic Gram-positive bacteria:

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

Aerobic Gram-negative bacteria:

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

Anaerobic bacteria:

Bacteroides fragilis, Bacteroides ovatus**, Bacteroides thetaiotaomicron**, Bacteroides vulgatus**, Clostridium difficile**.

Naturally resistant strains:

Aerobic Gram-positive bacteria: Enterococcus faecium.

* Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications.

** Naturally moderate susceptibility.

Other data:

Hospital-acquired infections caused by Pseudomonas aeruginosa may require combination therapy.

Pharmacokinetics.

Absorption.

There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration. After intravenous administration, the drug accumulates in bronchial mucosa, lung tissue and bronchial secretions (concentrations in lung tissue exceed those in blood plasma), and in urine. Levofloxacin penetrates poorly into cerebrospinal fluid.

Distribution.

Approximately 30–40% of levofloxacin is protein-bound in serum. There is virtually no accumulation effect with repeated administration of levofloxacin 500 mg once daily. A slight but predictable accumulation occurs after administration of 500 mg twice daily. Steady state is achieved within 3 days.

Penetration into tissues and body fluids.

Penetration into bronchial mucosa and bronchial secretions of lung tissue. Maximum concentrations of levofloxacin in bronchial mucosa and bronchial secretions of lung tissue after oral administration of 500 mg were 8.3 and 10.8 µg/mL, respectively. These levels were reached within 1 hour after drug administration.

Penetration into lung tissue. Maximum concentration of levofloxacin in lung tissue after oral administration of 500 mg was approximately 11.3 µg/g, reached 4–6 hours after drug administration. Concentrations in lung tissue exceed those in blood plasma.

Penetration into blister fluid (skin). Maximum concentrations of levofloxacin (4.0–6.7 µg/mL) in blister fluid were achieved within 2–4 hours after drug administration during 3 days of treatment with doses of 500 mg once or twice daily, respectively.

Penetration into cerebrospinal (spinal) fluid. Levofloxacin penetrates poorly into cerebrospinal fluid.

Penetration into prostate tissue. After administration of 500 mg levofloxacin once daily for 3 days, mean concentrations in prostate tissue reached 8.7 µg/g, 8.2 µg/g, and 2 µg/g at 2, 6, and 24 hours, respectively. The mean prostate/plasma concentration ratio was 1.84.

Concentration in urine. Mean urinary concentrations 8–12 hours after single oral doses of 150 mg, 300 mg, and 500 mg of levofloxacin were 44 mg/L, 91 mg/L, and 200 mg/L, respectively.

Biotransformation.

Levofloxacin undergoes minimal metabolism, with metabolites including desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the total drug 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 is 6–8 hours). It is primarily excreted by the kidneys (over 85% of the administered dose).

There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration, indicating that these routes of administration are interchangeable.

Linearity.

Levofloxacin exhibits linear pharmacokinetics in the dose range of 50–600 mg.

Patients with renal impairment.

Renal impairment affects the pharmacokinetics of levofloxacin. With reduced kidney function, renal excretion and clearance decrease, and elimination half-life increases, as shown in Table 2.

Table 2

Geriatric 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 of female and male patient groups demonstrated minor differences in the pharmacokinetics of levofloxacin depending on gender. There is no evidence that these gender differences in pharmacokinetics are clinically significant.

Clinical characteristics.

Indications.

Levoflor, infusion solution, is indicated for the treatment of the following infectious diseases in adults:

− 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 definitive treatment.

*Levofloxacin should be prescribed for the above-mentioned infectious diseases only when other antibacterial agents, primarily used for initial treatment of these infections, have shown insufficient efficacy.

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

Contraindications.

− Hypersensitivity to levofloxacin, to other quinolones, or to any component of the medicinal product.

− Tendon-related adverse reactions following previous administration of quinolones.

− Epilepsy.

− Pediatric population (under 18 years of age).

− Pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Theophylline, fenbufen, or similar nonsteroidal anti-inflammatory drugs (NSAIDs). A significant reduction in seizure threshold may occur with concomitant administration of quinolones and theophylline, NSAIDs, or other substances that lower the seizure threshold. The concentration of levofloxacin in the presence of fenbufen is approximately 13% higher than when levofloxacin is administered alone.

Probenecid and cimetidine.

Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin. Renal clearance of levofloxacin decreases by 34% in the presence of probenecid and by 24% with cimetidine. Therefore, both agents may block tubular excretion of levofloxacin. These should be used with caution in patients with renal impairment.

Cyclosporine.

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

Vitamin K antagonists.

When administered concomitantly with vitamin K antagonists (e.g., warfarin), coagulation test values (PT/INR) may increase. Severe bleeding may occur. Therefore, coagulation parameters should be monitored in patients receiving vitamin K antagonists concomitantly.

Medicinal products that prolong the QT interval.

Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving medicinal products that prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotic medicinal products).

Theophylline.

Levofloxacin does not affect the pharmacokinetics of theophylline, which is primarily metabolized via CYP1A2; therefore, levofloxacin is not considered an inhibitor of CYP1A2.

Glucocorticoids.

Concomitant use with glucocorticoids increases the risk of tendon rupture.

Other.

No clinically significant effect on the pharmacokinetics of levofloxacin has been observed when administered concomitantly with the following medicinal products: calcium carbonate, digoxin, glyburide (glibenclamide), ranitidine. Concomitant use of levofloxacin with alcohol is not recommended.

Special precautions for use.

The use of the 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 there are no alternative treatment options and after careful benefit/risk assessment.

Prolonged, disabling and potentially irreversible serious adverse reactions. In very rare cases, prolonged (lasting for months or years), disabling and potentially irreversible serious adverse reactions affecting various, and sometimes multiple simultaneously, body systems (musculoskeletal, nervous system, mental health and sensory organs) have been reported in patients receiving fluoroquinolones, regardless of age or existing risk factors. The medicinal product should be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.

Caution is advised when using the medicinal product in patients with severe renal function impairment, severe atherosclerosis of cerebral vessels, or cerebrovascular disorders. Renal and hepatic function should be monitored throughout the entire treatment course. Alcohol consumption should be avoided during treatment with the medicinal product. In very severe cases of pneumonia caused by pneumococci, levofloxacin may not provide optimal therapeutic effect. Hospital-acquired infections caused by Pseudomonas aeruginosa may require combination therapy.

Duration of infusion. The recommended duration of infusion for the 500 mg intravenous solution is at least 60 minutes. With ofloxacin, tachycardia and transient increase in blood pressure may occur during infusion. In rare cases, sudden drop in blood pressure and circulatory collapse may occur. If a marked decrease in blood pressure occurs during levofloxacin administration, the infusion should be stopped immediately. Aortic aneurysm and dissection, and cardiac valve regurgitation/insufficiency Epidemiological studies have reported an increased risk of aortic aneurysm and dissection (aortic 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 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 aneurysm and/or aortic dissection, or heart valve disease, or in the presence of other risk factors or predisposing conditions:

• for both aortic aneurysm and dissection and cardiac valve regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome or vascular Ehlers-Danlos syndrome, Turner syndrome, Takayasu arteritis, giant cell arteritis, Behçet’s disease, hypertension, rheumatoid arthritis, known atherosclerosis), or additionally:
• for aortic aneurysm and dissection (e.g., vascular disorders such as Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren’s syndrome), or additionally:

§ for cardiac valve regurgitation/insufficiency (e.g., infective endocarditis). The risk of aortic aneurysm, dissection and rupture may be increased in patients concurrently receiving systemic corticosteroids.

Patients should be advised to seek immediate medical attention in emergency departments if they experience sudden abdominal, chest or back pain. Patients should be advised to seek immediate medical help in case of acute dyspnea, new onset palpitations, or development of abdominal or lower limb edema. Methicillin-resistant Staphylococcus aureus (MRSA). Methicillin-resistant Staphylococcus aureus is likely to exhibit cross-resistance to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for treatment of known or suspected MRSA infections, except when laboratory testing confirms susceptibility of the pathogen to levofloxacin. E. coli resistance. Resistance of E. coli , the most common causative agent of urinary tract infections, to fluoroquinolones varies across different countries of the European Union. When prescribing levofloxacin, physicians should consider local prevalence of E. coli resistance to fluoroquinolones.

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

Tendinitis and tendon rupture. Tendinitis and tendon ruptures (not limited to the Achilles tendon), sometimes bilateral, may occur within 48 hours of starting quinolone or fluoroquinolone therapy and even several months after discontinuation of treatment in patients receiving 1000 mg daily doses of levofloxacin. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, patients with solid organ transplants, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of the medicinal product with corticosteroids should be avoided. If signs of tendinitis (e.g., painful swelling, inflammation) occur, treatment 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 occur.

Myoclonus.

Cases of myoclonus have been reported in patients receiving levofloxacin (see section "Adverse reactions"). The risk of myoclonus is increased in elderly patients and patients with renal impairment if the levofloxacin dose is not adjusted according to creatinine clearance. Levofloxacin should be discontinued immediately upon the first occurrence of myoclonus and appropriate treatment initiated.

Clostridium difficile-associated disease. Diarrhea, especially severe, persistent or with blood, during or after levofloxacin treatment may be a symptom of Clostridium difficile-associated disease, the most severe form of which is pseudomembranous colitis. If pseudomembranous colitis is suspected, levofloxacin should be discontinued immediately and appropriate treatment initiated (e.g., vancomycin). 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. As with other quinolones, the medicinal product should be used with extreme caution in patients predisposed to seizures, such as those with central nervous system disorders, concomitant therapy with phenylbutazone and similar medicinal products, or medicinal products that increase seizure susceptibility (lower the seizure threshold), such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If seizures occur, levofloxacin treatment should be discontinued.

Glucose-6-phosphate dehydrogenase deficiency. Patients with latent or manifest glucose-6-phosphate dehydrogenase deficiency are prone to hemolytic reactions when treated with quinolone antibacterial medicinal products; therefore, levofloxacin should be used with caution in such patients due to the possibility of hemolysis.

Renal impairment. Since levofloxacin is primarily eliminated via the kidneys, dose adjustment is required in patients with renal impairment (see section "Method of administration and dosage").

Hypersensitivity reactions. Levofloxacin may occasionally cause serious, potentially life-threatening hypersensitivity reactions (e.g., angioedema, anaphylactic shock), even after the first dose. If hypersensitivity reactions occur, levofloxacin should be discontinued, medical advice sought, and appropriate treatment initiated.

Severe bullous reactions. Severe skin adverse reactions (SCAR), including toxic epidermal necrolysis (TEN), also known as Lyell’s syndrome, Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal, have been reported. Patients should be informed about signs and symptoms of severe skin reactions and closely monitored. If such signs and symptoms appear, levofloxacin should be discontinued immediately and alternative therapy considered. If a patient develops a serious reaction such as SJS, TEN or DRESS while taking levofloxacin, reinitiation of levofloxacin treatment in this patient is absolutely contraindicated. Patients should be advised to seek immediate medical attention before continuing treatment if skin and/or mucosal reactions occur.

Blood glucose level changes. Changes in blood glucose levels (hyperglycemia and hypoglycemia) have been reported with quinolone use, particularly in diabetic patients receiving concomitant oral hypoglycemic agents (e.g., glibenclamide) or insulin. Cases of hypoglycemic coma have occurred. Diabetic patients should monitor their blood glucose levels.

Prevention of photosensitivity reactions. Photosensitivity reactions have been reported during levofloxacin treatment. To prevent photosensitivity reactions, patients taking levofloxacin should avoid sunlight exposure and UV radiation (UV lamps, tanning beds) during treatment and for 48 hours after discontinuation of levofloxacin. In patients taking vitamin K antagonists , coagulation parameters should be monitored during concomitant use of levofloxacin and vitamin K antagonists (warfarin) due to the potential risk of increased coagulation parameters (prothrombin time/INR) and/or bleeding.

Psychotic reactions. Psychotic reactions have been observed in patients receiving quinolones, including levofloxacin. In very rare cases, these progressed to suicidal ideation and self-destructive behavior, sometimes after only a single dose of levofloxacin. 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. Cases of QT interval prolongation have been reported with fluoroquinolone use. Caution should be exercised when using fluoroquinolones, including levofloxacin, in patients with known risk factors for QT interval prolongation:

− congenital or acquired long QT syndrome;

− concomitant use of medicinal products that prolong the QT interval (including class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics);

− electrolyte imbalances (particularly hypokalemia, hypomagnesemia);

− cardiac diseases (heart failure, myocardial infarction, bradycardia). Elderly patients are more sensitive to medicinal products that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used with caution in this patient group.

Peripheral neuropathy. Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia or weakness have been reported in patients receiving quinolones and fluoroquinolones. If symptoms of neuropathy such as pain, burning, tingling, numbness or weakness occur, patients should be instructed to inform their physician to prevent development of potentially irreversible conditions.

Hepatobiliary disorders. Cases of hepatic necrosis up to life-threatening liver failure have been reported with levofloxacin use, primarily in patients with severe underlying conditions such as sepsis (see section "Adverse reactions"). Patients should be advised to discontinue treatment and seek medical advice if signs of liver disease occur, such as anorexia, jaundice, dark urine, pruritus or abdominal pain.

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 in patients with myasthenia gravis during post-marketing use of fluoroquinolones. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances. If visual disturbances or other ocular effects occur, immediate consultation with an ophthalmologist is required.

Blood disorders.

Bone marrow suppression, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia or agranulocytosis, may develop during levofloxacin treatment (see section "Adverse reactions"). If any of these disorders are suspected, blood counts should be monitored. If abnormal results are obtained, discontinuation of levofloxacin treatment should be considered. Superinfection. Use of levofloxacin, particularly over prolonged periods, may lead to overgrowth of microorganisms not susceptible to the drug. If superinfection develops during therapy, 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 results using more specific methods may be necessary. Levofloxacin may inhibit the growth of Mycobacterium tuberculosis , potentially leading to false-negative results in bacteriological testing of patients with tuberculosis.

Important information about excipients.

This medicinal product contains 860 mg of sodium per dose. Caution is advised when administering the product to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Due to lack of studies and the potential for quinolones to damage developing joint cartilage, the medicinal product is contraindicated during pregnancy and breastfeeding. If pregnancy occurs during treatment with the medicinal product, this should be reported to the physician.

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

Ability to affect reaction speed when driving or operating machinery.

Some adverse reactions (e.g., dizziness/vertigo, somnolence, visual disturbances) may impair a patient's ability to concentrate and reaction speed, thereby increasing risk in situations where these abilities are particularly important (e.g., when driving or operating machinery).

Dosage and Administration

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

The medicinal product should be administered intravenously, slowly, 1–2 times daily by infusion. The administration of 1 vial of levofloxacin (100 mL of solution for intravenous infusion containing 500 mg levofloxacin) should take not less than 60 minutes.

Mixing with infusion solutions.

The medicinal product is compatible with the following infusion solutions:

0.9% sodium chloride solution, 5% glucose monohydrate solution, 2.5% dextrose in Ringer's solution, multi-component solutions for parenteral nutrition (amino acids, carbohydrates, electrolytes). The solution should be used within 3 hours after vial puncture. Treatment with levofloxacin, after initial intravenous administration, may be completed with oral formulation, provided such treatment is appropriate for the individual patient.

Due to the bioequivalence of parenteral and oral dosage forms, the same dose may be used. The duration of treatment depends on the course of the disease. As with other antibacterial agents, it is recommended to continue administration of the drug for at least 48–72 hours after normalization of body temperature or until microbiological testing has confirmed eradication of the pathogen.

Dosage for adult patients with normal renal function, in whom creatinine clearance is greater than 50 mL/min, is given in Table 3.

Table 3

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

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

Dosage recommendations for adult patients with renal impairment, in whom creatinine clearance is less than 50 ml/min, are shown in Table 4.

Table 4

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 normal, there is no need for dose adjustment.

Pediatric population.

The medicinal product is contraindicated in children, as damage to articular cartilage cannot be excluded.

Overdose.

Symptoms: dizziness, disturbance/confusion of consciousness, seizures, myoclonus, tremor, QT interval prolongation.

Treatment. In case of overdose, close monitoring of the patient, including ECG, is required. Treatment is symptomatic. Hemodialysis, including peritoneal dialysis and CAPD, is not effective in removing levofloxacin from the body. There are no specific antidotes.

Side effects

Side effects are listed by system organ class and frequency: 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 the available data).

Within each group, side effects are listed in order of decreasing severity.

Eye disorders*: rare – visual disturbances such as blurred vision; frequency not known – transient loss of vision, uveitis.

Ear and labyrinth disorders*: uncommon – vertigo; rare – tinnitus; frequency not known – hearing impairment, hearing loss.

Respiratory, thoracic and mediastinal disorders: uncommon – dyspnea; frequency not known – bronchospasm, allergic pneumonitis.

Gastrointestinal disorders: common – diarrhea, vomiting, nausea; uncommon – abdominal pain, dyspepsia, flatulence, constipation; frequency not known – hemorrhagic diarrhea, which may indicate enterocolitis, including pseudomembranous colitis; pancreatitis.

Hepatobiliary disorders: common – increased liver enzyme levels (ALT/AST, alkaline phosphatase, GGT); uncommon – increased blood bilirubin; frequency not known – jaundice and severe hepatic damage, including cases of acute liver failure, predominantly in patients with severe underlying diseases, hepatitis.

Renal and urinary disorders: uncommon – increased serum creatinine levels; frequency not known – acute renal failure (e.g., due to interstitial nephritis).

Metabolism and nutrition disorders: uncommon – anorexia; rare – hypoglycemia, particularly in diabetic patients; frequency not known – hyperglycemia, hypoglycemic coma. Signs of hypoglycemia may include increased appetite, nervousness, excessive sweating, and limb tremors.

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

Nervous system disorders*: common – headache, dizziness; uncommon – somnolence, tremor, dysgeusia; rare – seizures, paresthesia; frequency not known – myoclonus, peripheral sensory or sensorimotor neuropathy, tactile disturbances, parosmia including anosmia, dyskinesia, extrapyramidal disorders, other movement coordination disorders including gait disturbances, ataxia, ageusia, loss of consciousness, benign intracranial hypertension.

Psychiatric disorders*: common – insomnia; uncommon – anxiety, confusion, irritability, restlessness; rare – psychotic disorders (including hallucinations, paranoia), depression, agitation, pathological dreams, nightmares, feeling of fear; frequency not known – mania, psychotic disorders with self-destructive behavior, including suicidal ideation or actions.

Cardiac disorders**: rare – tachycardia, palpitations; frequency not known – ventricular tachycardia, which may lead to cardiac arrest; ventricular arrhythmia and torsade de pointes (mainly in patients with risk factors for QT interval prolongation), QT interval prolongation on ECG, arterial hypotension, collapse, vasculitis, phlebitis. Aneurysm, aortic dissection, regurgitation/insufficiency of any cardiac valve. Blood and lymphatic system disorders: uncommon – leukopenia, eosinophilia; rare – neutropenia, thrombocytopenia, which may cause increased tendency to hemorrhage or bleeding; frequency not known – bone marrow failure, including aplastic anemia, pancytopenia, agranulocytosis, hemolytic anemia.

Immune system disorders: rare – angioedema, hypersensitivity reactions, including anaphylactic shock, anaphylactoid shock (anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose).

Skin and subcutaneous tissue disorders: uncommon – rash, pruritus, urticaria, skin erythema, hyperhidrosis; rare – drug reaction with eosinophilia and systemic symptoms (DRESS), persistent drug erythema; frequency not known – skin hyperpigmentation, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme exudativum, photosensitivity reactions, increased sensitivity to sunlight and ultraviolet radiation, leukocytoclastic vasculitis, stomatitis.

Musculoskeletal and connective tissue disorders*: uncommon – arthralgia, myalgia; rare – tendon disorders, including tendinitis (e.g., Achilles tendon), muscle weakness, which may be particularly significant in patients with severe myasthenia gravis; frequency not known – rhabdomyolysis, tendon, ligament or muscle rupture, arthritis.

Infections and infestations: uncommon – fungal infections, including Candida species, pathogenic microorganism resistance.

General disorders and administration site conditions*: common – injection site reaction, including erythema and pain; uncommon – asthenia; rare – increased body temperature; frequency not known – general weakness, pain (including back, chest and limb pain); as with other fluoroquinolones, porphyria attacks may occur in patients with porphyria.

* Very rare cases of prolonged (up to months or years), disabling and potentially irreversible serious adverse reactions affecting multiple, sometimes multiple, organ system classes and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, in some cases neuropathy associated with paresthesia, depression, fatigue, memory impairment, sleep disorders, and hearing, vision, taste and smell disturbances) have been associated with the use of quinolones and fluoroquinolones, regardless of previously existing risk factors (see section "Special precautions"); anxiety, suicidal thoughts, panic attacks, neuralgia, and attention concentration disturbances have also been reported as potential aspects of prolonged and disabling fluoroquinolone-induced adverse reactions that may lead to loss of work capacity.

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

Reporting 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 are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

After opening the vial, store at room temperature for 3 days. After perforation of the rubber stopper: use immediately (within 3 hours).

Storage conditions.

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

Incompatibilities.

The solution should not be mixed with heparin or alkaline solutions (e.g., sodium bicarbonate). The solution may only be mixed with medicinal products listed in the section "Dosage and administration".

Packaging.

100 ml in a vial; 1 vial in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

VEM Ilac San. ve Tik. A.S.

Manufacturer's address and location of its business operations.

Cerkezkoy Organize Sanayi Bolgesi, Karaagac Mahallesi, Fatih Boulevard No: 38 Kapakli / Tekirdag / Turkey.