Levoximed

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

Composition:

Active substance: levofloxacin;

1 tablet contains levofloxacin (as levofloxacin hemihydrate) 500 mg;

Excipients: microcrystalline cellulose, hydroxypropylmethylcellulose, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating composition: Opadry® II Yellow (85G32281): polyvinyl alcohol, talc, titanium dioxide (E 171), polyethylene glycol, lecithin, yellow iron oxide (E 172), IA63400/IC07484 talc/red iron oxide (E 172) (3:1).

Medicinal form. Film-coated tablets.

Main physicochemical properties: elongated, film-coated tablets, light peach-colored, with a break line on one side.

Pharmacotherapeutic group.

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

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone group, the S(-) enantiomer of the racemic mixture of the drug ofloxacin.

Mechanism of action

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

Pharmacokinetic/pharmacodynamic relationship

The degree of antibacterial activity of levofloxacin depends on the ratio of the maximum serum concentration (C_max) or the area under the concentration-time curve (AUC) to the minimum inhibitory concentration (MIC).

Mechanism of resistance development

Resistance to levofloxacin develops gradually due to mutations in the target site of type II topoisomerases, DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as penetration barriers (typical for Pseudomonas aeruginosa) and efflux mechanisms, may also affect susceptibility to levofloxacin.

Cross-resistance between levofloxacin and other fluoroquinolones is observed. Due to the mechanism of action, cross-resistance between levofloxacin and other classes of antibacterial agents is usually not present.

Clinical breakpoints

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

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

1 Only uncomplicated urinary tract infections.

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

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

Generally 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.

Absorption

After oral administration, levofloxacin is rapidly and almost completely absorbed, with peak plasma concentrations reached within 1–2 hours. Absolute bioavailability is 99–100%. Food intake slightly affects its absorption. Steady-state levels are achieved within 48 hours after administration of 500 mg levofloxacin 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 good tissue penetration throughout the body.

Penetration into tissues and body fluids

Levofloxacin has been shown to penetrate into bronchial mucosa, epithelial lining fluid, alveolar macrophages, lung tissue, skin (vesicle content), prostate tissue, and urine. However, penetration of levofloxacin into cerebrospinal fluid is poor.

Metabolism

Levofloxacin undergoes minimal metabolism. Metabolites include desmethyl-levofloxacin and levofloxacin N-oxide, which account for less than 5% of the administered dose excreted in urine. The levofloxacin molecule is stereochemically stable and does not undergo chiral inversion.

Elimination

After oral administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6–8 hours). Elimination occurs primarily via the kidneys (over 85% of the administered dose). Mean apparent total clearance of levofloxacin after a single 500 mg dose is 175 ± 29.2 mL/min. There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration, indicating interchangeability of these routes.

Linearity

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

Special populations

Patients with renal impairment

Renal impairment affects the pharmacokinetics of levofloxacin. With decreased renal function, renal elimination and creatinine clearance are reduced, and elimination half-life is prolonged.

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

Elderly patients

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

Gender differences

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

Clinical characteristics.

Indications.

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

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

Treatment of the following infections when use of other antibacterial agents, typically prescribed for initial treatment of these infections, is not possible:

• Acute bacterial sinusitis;
• Acute exacerbation of chronic obstructive pulmonary disease, including chronic bronchitis;
• Community-acquired pneumonia;
• Complicated skin and soft tissue infections;
• Uncomplicated cystitis (see section “Special precautions”).

The drug may be used to complete the treatment course in patients who have shown improvement during initial therapy with intravenous levofloxacin.

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

Contraindications.

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

Interaction with other medicinal products and other types of interactions.

Iron salts, zinc salts, antacids containing magnesium and aluminium, didanosine

Significant reduction in levofloxacin absorption may occur when administered concomitantly with iron salts and antacids containing magnesium or aluminium, or didanosine (only for formulations containing buffering agents of aluminium or magnesium). Concurrent administration of fluoroquinolones with multivitamins containing zinc results in reduced oral absorption. Levofloxacin should be taken at least 2 hours after administration of products containing divalent or trivalent cations, such as iron salts, or antacids containing magnesium or aluminium. Calcium carbonate has minimal effect on the absorption of orally administered levofloxacin.

Sucralfate

Significant reduction in the bioavailability of levofloxacin may occur when administered concomitantly. Sucralfate should be taken 2 hours after levofloxacin administration.

Theophylline, fenbufen or similar nonsteroidal anti-inflammatory drugs (NSAIDs), and other agents that lower the seizure threshold

A marked decrease in seizure threshold may occur when administered concomitantly. No pharmacokinetic interaction between levofloxacin and theophylline has been observed. Levofloxacin concentrations were approximately 13% higher when administered with fenbufen compared to levofloxacin alone.

Probenecid, cimetidine, and other agents affecting tubular secretion

Reduced elimination of levofloxacin (due to inhibition of tubular secretion) may occur when administered concomitantly. Renal clearance of levofloxacin decreases by 24% with cimetidine and by 34% with probenecid. However, in studies, statistically significant kinetic differences did not have clinical relevance. Levofloxacin should be used with caution when administered concomitantly with medicinal products affecting tubular secretion, especially in patients with renal impairment.

Cyclosporine

The elimination half-life of cyclosporine increases by 33%.

Vitamin K antagonists

When administered concomitantly with vitamin K antagonists (e.g., warfarin), increased international normalized ratio (INR) and/or bleeding, which may be severe, have been reported. Coagulation parameters should be monitored when levofloxacin is used concomitantly with vitamin K antagonists.

Medicinal products that prolong the QT interval

Prolongation of the QT interval may occur when administered concomitantly. Levofloxacin should be used with caution when administered concomitantly with medicinal products capable of prolonging the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, and antipsychotics).

Other interactions

No influence of levofloxacin was observed when administered concomitantly with calcium carbonate, digoxin, glyburide, or ranitidine.

No effect of levofloxacin on the pharmacokinetics of theophylline (a marker substrate for the CYP1A2 enzyme) was 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 quinolones or fluoroquinolone-containing agents (see section "Adverse reactions"). Treatment of such patients should be initiated only if there are no alternative treatment options and after careful benefit/risk assessment (see also section "Contraindications").

Risk of resistance

There is a very high likelihood of co-resistance to fluoroquinolones, including levofloxacin, in methicillin-resistant Staphylococcus aureus (MRSA). Therefore, the drug is not recommended for the treatment of infections known or suspected to be caused by MRSA, except in cases where laboratory test results have confirmed pathogen susceptibility to levofloxacin.

The drug may be used for the treatment of acute bacterial sinusitis and acute exacerbation of chronic bronchitis, provided these infections have been appropriately diagnosed.

Resistance to fluoroquinolones in Escherichia coli (the most common causative agent of urinary tract infections) varies across different countries. Local prevalence of Escherichia coli resistance to fluoroquinolones should be taken into account when prescribing fluoroquinolones.

For the pulmonary form of anthrax, use is based on in vitro susceptibility data for Bacillus anthracis, experimental animal data, and limited human data. Physicians should consider national and/or international consensus guidelines on the treatment of anthrax.

Prolonged, disabling, and potentially irreversible serious adverse reactions

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

Tendinitis and tendon rupture

Tendinitis and tendon rupture (not limited to the Achilles tendon, sometimes bilateral) may occur within 48 hours of starting quinolone or fluoroquinolone therapy and have also been reported several months after discontinuation of treatment (see section "Adverse reactions"). The risk of tendinitis and tendon rupture is increased in elderly patients, patients with impaired renal function, patients who have undergone solid organ transplantation, and patients receiving concomitant corticosteroids. Therefore, concomitant use of corticosteroids should be avoided.

At the first signs of tendinitis (e.g., painful swelling, inflammation), treatment with the drug should be discontinued, and alternative therapy should be considered. The affected limb(s) should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy occur.

Myoclonus risk

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, particularly severe, persistent, and/or hemorrhagic, during or after levofloxacin use (even several weeks after treatment) may be a symptom of Clostridium difficile-associated disease, the most severe form of which is pseudomembranous colitis. Clostridium difficile-associated disease may range in severity from mild to life-threatening; pseudomembranous colitis being the most severe form. It is therefore important to consider this diagnosis in patients who develop severe diarrhea during or after treatment with levofloxacin. If Clostridium difficile-associated disease is suspected, the drug 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 drug is contraindicated in patients with a history of epilepsy. As with other quinolones, the drug should be used with extreme caution in patients predisposed to seizures, such as those with central nervous system disorders, patients receiving fenbufen or similar NSAIDs, or other drugs that increase seizure susceptibility (lower the seizure threshold), such as theophylline. If seizures occur, treatment with the drug should be discontinued.

Use in patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or known defects in glucose-6-phosphate dehydrogenase activity may be susceptible to hemolytic reactions during treatment with quinolone antibacterial agents; therefore, the drug should be used with caution in such patients, and monitoring for possible hemolysis is recommended.

Use in patients with renal impairment

Since levofloxacin is primarily excreted by the kidneys, dose adjustment is required in patients with renal impairment (renal insufficiency).

Hypersensitivity reactions

Serious, potentially fatal hypersensitivity reactions (from angioneurotic edema to anaphylactic shock) may occur during levofloxacin use, even after the first dose. If such reactions occur, the drug should be discontinued immediately, medical attention sought, and appropriate treatment initiated.

Severe bullous reactions

Severe skin adverse reactions, including toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with levofloxacin use, which may be life-threatening or fatal (see section "Adverse reactions"). Patients should be informed of the possible signs and symptoms of severe skin reactions and monitored closely. If signs or symptoms suggestive of such reactions occur, the drug should be discontinued immediately and alternative therapy considered. If a patient has experienced severe skin adverse reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, or drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) during levofloxacin use, levofloxacin treatment must never be repeated at any time.

Hypoglycemia risk

Alterations in blood glucose levels (hyperglycemia, hypoglycemia) have been reported during treatment with quinolones, including levofloxacin, particularly in diabetic patients receiving concomitant oral hypoglycemic agents (including glibenclamide) or insulin. Cases of hypoglycemic coma have been documented. Blood glucose levels should be monitored in diabetic patients during treatment with the drug (see section "Adverse reactions"). If changes in plasma glucose levels occur, the drug should be discontinued immediately and alternative antibiotic therapy not belonging to the fluoroquinolone class considered.

Photosensitization

Photosensitization may rarely occur during levofloxacin use. 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 the drug.

Use in patients taking vitamin K antagonists

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

Psychotic disorders

Psychotic reactions have been reported during treatment with quinolones, including levofloxacin. In very rare cases, these progressed to suicidal thoughts and self-destructive behavior, sometimes after only a single dose of levofloxacin. If such reactions occur, the drug should be discontinued and appropriate measures taken. The drug should be used with caution in patients with psychotic disorders or a history of psychiatric illness.

QT interval prolongation

The drug 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).

Female patients and elderly patients may be more sensitive to drugs that prolong the QT interval. The drug should be used with caution in these patient groups.

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hyposthesia, 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 the development of a potentially irreversible condition (see section "Adverse reactions").

Hepatobiliary disorders

Cases of necrotic hepatitis up to life-threatening liver failure have been observed during levofloxacin use, primarily in patients with severe underlying conditions such as sepsis. The drug should be discontinued and medical advice sought if signs and symptoms of liver disease such as anorexia, jaundice, dark urine, pruritus, or abdominal pain occur.

Exacerbation of myasthenia gravis

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

Visual disturbances

If visual disturbances or other ocular effects occur during treatment, patients should seek immediate ophthalmological evaluation.

Superinfection

With levofloxacin use, particularly prolonged use, opportunistic infections and overgrowth of resistant microorganisms may occur. Appropriate measures should be taken if superinfection develops during treatment.

Effect on laboratory tests

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

Levofloxacin suppresses the growth of Mycobacterium tuberculosis, so false-negative results may occur in bacteriological testing of patients with tuberculosis.

Aortic aneurysm/dissection and cardiac valve regurgitation/insufficiency

Epidemiological studies report an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and aortic and mitral valve regurgitation following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any cardiac valve have been reported in patients receiving fluoroquinolones (see section "Adverse reactions").

Therefore, fluoroquinolones should be used only after careful benefit/risk assessment and consideration of alternative therapeutic options in patients with a positive family history of aneurysm or congenital heart valve defects, or in patients with an 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, rheumatoid arthritis, or additionally
• for aortic aneurysm/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 and dissection and their 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 dyspnea, a new episode of palpitations, or development of abdominal or lower limb edema occurs.

Acute pancreatitis risk

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, acute abdominal pain, or vomiting should be evaluated immediately. If acute pancreatitis is suspected, the medicinal product should be discontinued. If the diagnosis is confirmed, the medicinal product must not be restarted. 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 treatment (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.

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 articular cartilage in the growing organism, the drug is contraindicated during pregnancy. If pregnancy occurs during treatment with the drug, it should be reported to the physician.

Breastfeeding period

Data on the excretion of levofloxacin into breast milk are 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, the drug is contraindicated during breastfeeding.

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

Levofloxacin has a negligible 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 car or operating machinery).

Dosage and Administration.

The medication is intended for oral use. Tablets should be swallowed whole with sufficient amount of liquid, without chewing. The drug may be taken regardless of food intake.

The medication should be administered at least 2 hours before or after administration of iron salts, zinc salts, antacids containing magnesium or aluminum, didanosine (only for formulations containing aluminum or magnesium in buffering agents), and sucralfate.

The medication may be used to complete the treatment course in patients who have demonstrated improvement during initial therapy with levofloxacin infusion solution, using the same dosage regimen.

Dosage depends on the type and severity of infection and on susceptibility of the likely pathogen.

Recommended Dosage.

Table 2

Patients with normal renal function (creatinine clearance >50 mL/min)

Table 3

Patients with renal function impairment (creatinine clearance – less than 50 ml/min)

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

Patients with hepatic impairment

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

Elderly patients

If renal function is not impaired, dose adjustment is not necessary in these patients.

Children

The drug is contraindicated in children (under 18 years of age).

Overdose

Symptoms: central nervous system disorders (confusion, dizziness, altered consciousness, seizures, myoclonus, hallucinations, and tremor); gastrointestinal disturbances (nausea and mucosal erosions); possible QT interval prolongation.

During post-marketing studies, the following adverse effects on the CNS were observed: confusion, convulsions, hallucinations, and tremor.

Treatment: symptomatic therapy. ECG monitoring should be performed, as QT interval prolongation may occur. Antacid agents should be used to protect gastric mucosa. Hemodialysis, including peritoneal dialysis or CAPD, is not effective for removing levofloxacin from the body. There is no specific antidote.

Side effects

The frequency of adverse reactions was determined according to the following criteria: very common (> 1/10), common (from > 1/100 to < 1/10), uncommon (from > 1/1000 to < 1/100), rare (from > 1/10000 to < 1/1000), very rare (> 1/10000), frequency not known (cannot be estimated from the available data).

Infections and infestations:

Uncommon – fungal infections (including Candida species), pathogenic microorganism resistance.

Blood and lymphatic system disorders:

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

Immune system disorders:

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

Endocrine system disorders:

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

Metabolism and nutrition disorders:

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

Mental disorders **:

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

Nervous system disorders **:

Common – headache, dizziness; uncommon – somnolence, tremor, dysgeusia; rare – seizures (see sections "Contraindications" and "Special precautions for use"), paresthesia, memory impairment; frequency not known – peripheral sensory or sensorimotor neuropathy, parosmia (including anosmia), dyskinesia, extrapyramidal disorders, ageusia, syncope, benign intracranial hypertension, myoclonus.

Eye disorders **:

Rare – visual disturbances such as blurred vision; frequency not known – transient loss of vision (see section "Special precautions for use"), uveitis.

Ear and labyrinth disorders **:

Uncommon – vertigo; rare – tinnitus; frequency not known – hearing impairment, hearing loss.

Cardiac disorders ***:

Rare – tachycardia, palpitations; frequency not known – ventricular tachycardia (which 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 ECG (see sections "Special precautions for use": QT interval prolongation, and "Overdose").

Vascular disorders ***:

Rare – arterial hypotension.

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

Hepatobiliary disorders:

Common – increased plasma 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 for use"), hepatitis.

Skin and subcutaneous tissue disorders****:

Uncommon – rash, pruritus, urticaria, hyperhidrosis; rare – drug rash 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 section "Special precautions for use"), leukocytoclastic vasculitis, stomatitis, skin hyperpigmentation.

Musculoskeletal and connective tissue disorders **:

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

Uncommon – asthenia; rare – pyrexia; frequency not known – pain, including back, chest, and extremity pain.

Other adverse reactions associated with fluoroquinolone use include porphyria attacks in patients with existing porphyria.

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

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

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

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

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

5 years.

Storage conditions.

Store at temperatures not exceeding 25 °C, in a place inaccessible to children.

Packaging.

7 tablets in a blister; 1 blister in a cardboard box.

Prescription status.

Prescription only.

Marketing authorization holder.

WORLD MEDICINE LLC, Ukraine.

Manufacturer.

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

Manufacturer's address and location of business activity.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.