Tygeron

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TIGERON® (TIGERON®)

Composition:

Active substance: levofloxacin;

1 tablet contains levofloxacin hemihydrate equivalent to 500 mg or 750 mg of levofloxacin;

Excipients: povidone K29/32, microcrystalline cellulose, crospovidone, magnesium stearate, colloidal anhydrous silicon dioxide, Opadry 03B84681 pink coating: hypromellose, titanium dioxide (E 171), polyethylene glycol, iron oxide red (E 172), iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: capsule-shaped, film-coated tablets of pink color with "500" or "750" embossed on one side.

Pharmacotherapeutic group.

Antibacterial agents of the quinolone group. Fluoroquinolones. ATC code J01M A12.

Pharmacological properties.

Pharmacodynamics.

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

Mechanism of action.

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

Pharmacokinetic/pharmacodynamic relationship.

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

Mechanism of resistance.

Resistance to levofloxacin develops through a stepwise mutation process at the target site in both types of topoisomerase II: DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as reduced permeability (common in Pseudomonas aeruginosa) and efflux mechanisms, may also affect susceptibility to levofloxacin.

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

Clinical breakpoints.

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

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

Pathogen	Susceptible	Resistant
Enterobacteriaceae	≤0.5 mg/l	>1 mg/l
Pseudomonas spp.	≤0.001 mg/l	>1 mg/l
Acinetobacter spp.	≤0.5 mg/l	>1 mg/l
Staphylococcus aureus Coagulase-negative staphylococci	≤0.001 mg/l	>1 mg/l
Enterococcus spp.1	≤4 mg/l	>4 mg/l
Streptococcus pneumoniae	≤0.001 mg/l	>2 mg/l
Streptococcus A, B, C, G	≤0.001 mg/l	>2 mg/l
Haemophilus influenzae	≤0.06 mg/l	>0.06 mg/l
Moraxella catarrhalis	≤0.125 mg/l	>0.125 mg/l
Helicobacter pylori	≤1 mg/l	>1 mg/l
Aerococcus sanguinicola and urinae 2	≤2 mg/l	>2 mg/l
Aeromonas spp.	≤0.5 mg/l	>1 mg/l
Pharmacokinetic/pharmacodynamic (non-species-related) breakpoints	≤0.5 mg/l	>1 mg/l
1 Only uncomplicated urinary tract infections. 2 Inference on susceptibility may be based on susceptibility to ciprofloxacin.

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

Usually susceptible species Aerobic gram-positive bacteria: Bacillus anthracis, Staphylococcus aureus methicillin-susceptible, Staphylococcus saprophyticus, Streptococcus groups C and G, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes. Aerobic gram-negative bacteria: Eikenella corrodens, Haemophilus influenzae, Haemophilus para-influenzae, Klebsiella oxytoca, Moraxella catarrhalis, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri. Anaerobic bacteria: Peptostreptococcus. Others: Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamydia trachomatis, Legionella pneumophila, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum. Species for which acquired resistance may be a problem Aerobic gram-positive bacteria: Enterococcus faecalis, Staphylococcus aureus methicillin-resistant*, coagulase-negative Staphylococcus spp. Aerobic gram-negative bacteria: Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens. Anaerobic bacteria: Bacteroides fragilis. Naturally resistant strains Aerobic gram-positive bacteria: Enterococcus faecium.

*Methicillin-resistant S. aureus is highly likely to exhibit co-resistance to fluoroquinolones, including levofloxacin.

Pharmacokinetics.

Absorption.

Orally administered levofloxacin is rapidly and almost completely absorbed; peak plasma concentrations (Cmax) are reached within 1–2 hours. Absolute bioavailability is 99–100%.

Food has minimal effect on the absorption of levofloxacin.

Steady-state concentrations are achieved within 48 hours with a dosing regimen of 500 mg once or twice daily.

Distribution.

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

Penetration into tissues and body fluids.

Penetration of levofloxacin has been demonstrated into bronchial mucosa, bronchial secretions, lung tissue, alveolar macrophages, skin (blister fluid), prostate tissue, and urine. However, levofloxacin penetrates poorly into cerebrospinal fluid.

Metabolism.

Levofloxacin undergoes minimal metabolism. The metabolites identified are desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for < 5% of the administered dose and are excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.

Elimination.

Following both oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life (t1/2) is 6–8 hours). It is excreted predominantly by the kidneys (>85% of the administered dose). The mean total clearance of levofloxacin after a single 500 mg oral dose was 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 dose range of 50–1000 mg.

Patients with renal impairment.

The pharmacokinetics of levofloxacin are affected by the degree of renal impairment. With declining renal function, renal excretion and clearance decrease, and t1/2 increases, as shown in the table below.

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

Creatinine clearance (ml/min)	<20	20-49	50-80
Renal clearance (ml/min)	13	26	57
t1/2 (hours)	35	27	9

Geriatric 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 in male and female patients has 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.

The drug is indicated in adults for the treatment of the following infections (see sections “Pharmacodynamics” and “Special precautions”):

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

The drug should be used only when it is considered inappropriate to use antibacterial agents usually recommended for initial treatment of the following infections:

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

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

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

Contraindications.

Hypersensitivity to levofloxacin, other quinolones, or to any excipients of the drug.

Epilepsy.

History of tendon disorders associated with fluoroquinolone administration.

Age under 18 years.

Pregnancy and lactation.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on levofloxacin

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

Absorption of levofloxacin is significantly reduced when administered concomitantly with iron salts or antacids containing magnesium or aluminium, or with didanosine (only formulations containing aluminium or magnesium buffering agents). Concurrent administration of fluoroquinolones with multivitamins containing zinc results in reduced oral absorption. It is not recommended to take medicinal products containing divalent or trivalent cations, such as iron salts, zinc salts, antacids containing magnesium or aluminium, or didanosine (only for didanosine formulations containing aluminium or magnesium buffering agents) within 2 hours before or after levofloxacin administration (see section “Dosage and administration”). Calcium salts had minimal effect on the oral absorption of levofloxacin.

Sucralfate.

The bioavailability of levofloxacin is significantly reduced when administered concomitantly with sucralfate. If a patient requires both sucralfate and levofloxacin, it is preferable to take sucralfate 2 hours after levofloxacin administration (see section “Special precautions”).

Theophylline, fenbufen or similar non-steroidal 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 with theophylline, non-steroidal anti-inflammatory drugs, and other agents that reduce 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 levofloxacin elimination. Renal clearance of levofloxacin is reduced by cimetidine (24%) and probenecid (34%). This occurs because both agents can block tubular secretion of levofloxacin. Nevertheless, statistically significant kinetic differences are unlikely to have clinical significance. Levofloxacin should be administered with caution together with agents affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other significant information.

No clinically significant effect on the pharmacokinetics of levofloxacin has been observed when administered concomitantly with calcium carbonate, digoxin, glyburide, or ranitidine.

Effect of levofloxacin on other medicinal products

Cyclosporine.

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

Vitamin K antagonists.

When administered concomitantly with vitamin K antagonists (e.g., warfarin), increased values of coagulation tests (INR/PT) and/or bleeding, which may be severe, have been reported. Therefore, patients receiving concomitant vitamin K antagonists should be monitored for coagulation parameters (see section “Special precautions”).

Medicinal products that prolong the QT interval.

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

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

Other types of interactions

Food.

No clinically significant interaction with food has been observed. Therefore, the drug can be administered independently of food intake.

Special precautions for use.

Levofloxacin should be avoided in patients who have previously experienced serious adverse reactions to quinolone or fluoroquinolone-containing medicinal products (see section "Adverse reactions"). Treatment with levofloxacin in such patients should only be initiated if no alternative treatment options are available and after careful assessment of the benefit-risk ratio (see section "Contraindications").

Methicillin-resistant Staphylococcus aureus.

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

Levofloxacin 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 pathogen in urinary tract infections) varies across different countries. Local prevalence of Escherichia coli resistance to fluoroquinolones should be taken into account when prescribing fluoroquinolones.

Pulmonary form of anthrax.

The use of the drug for treatment in humans is based on in vitro data on susceptibility of Bacillus anthracis, experimental animal data, and limited human treatment data. Physicians should refer to national and/or international consensus treatment guidelines for anthrax.

Prolonged, disabling and potentially irreversible serious adverse reactions.

Rare cases of prolonged (lasting months or years), disabling and potentially irreversible serious adverse reactions affecting one or sometimes multiple body systems (musculoskeletal, nervous, psychiatric systems and sensory organs) have been reported in patients receiving quinolones or fluoroquinolones, regardless of age or pre-existing risk factors. If any signs or symptoms of a serious adverse reaction occur, levofloxacin should be discontinued immediately and medical advice should be sought.

Tendinitis and tendon rupture.

Tendinitis and tendon rupture (particularly of the Achilles tendon, although not exclusively) may occur within 48 hours of starting quinolone or fluoroquinolone therapy, or even several months after discontinuation of therapy. Elderly patients, those with renal impairment or organ transplants, patients receiving more than 1000 mg of levofloxacin per day, and those taking corticosteroids are at higher risk of developing tendinitis and tendon rupture. Therefore, concomitant use of corticosteroids with levofloxacin should be avoided.

If early signs of tendinitis (e.g., inflammation and swelling accompanied by pain) occur, levofloxacin 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 in patients with renal impairment if the dose of levofloxacin 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 treatment with the drug (including several weeks after treatment) may be a symptom of disease caused by Clostridium difficile (CDAD). The severity of CDAD may range from mild to life-threatening; the most severe form is pseudomembranous colitis (see section "Adverse reactions"). It is therefore important to consider this diagnosis in patients who develop severe diarrhea during or after treatment with levofloxacin. If CDAD is suspected or confirmed, the drug should be discontinued immediately and appropriate therapy initiated without delay. Antiperistaltic medicinal products 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 (see section "Contraindications") and, as with other quinolones, should be used with extreme caution in patients predisposed to seizures or when used concomitantly with substances 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"), treatment with levofloxacin should be discontinued.

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 when treated with quinolone antibacterial agents. Therefore, if levofloxacin must be used in such patients, monitoring for possible hemolysis is recommended.

Patients with renal impairment.

Since levofloxacin is primarily excreted by the kidneys, the dose should be adjusted in patients with impaired renal function (see section "Dosage and administration").

Hypersensitivity reactions.

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

Severe skin reactions.

Severe skin reactions, which may be life-threatening or fatal, including toxic epidermal necrolysis (TEN, also known as Lyell's syndrome), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported during treatment with levofloxacin (see section "Adive reactions"). Patients should be informed about the signs and symptoms of severe skin reactions and monitored closely. If signs or symptoms suggestive of these reactions occur, levofloxacin treatment should be discontinued immediately and alternative therapy considered. If a patient develops one of these serious adverse reactions (e.g., SJS, TEN, or DRESS syndrome) during treatment with levofloxacin, re-initiation of levofloxacin therapy is absolutely contraindicated.

Blood glucose alterations.

Alterations in blood glucose levels (including both hyperglycemia and hypoglycemia) have been reported during treatment with quinolones, particularly in patients with diabetes mellitus who are concurrently receiving oral hypoglycemic agents (e.g., glyburide) or insulin. Cases of hypoglycemic coma have been documented. Blood glucose levels should be monitored in diabetic patients (see section "Adverse reactions"). If a patient reports disturbances in blood glucose levels, levofloxacin treatment should be discontinued immediately and alternative antibacterial therapy considered.

Phototoxicity prevention.

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

Patients receiving vitamin K antagonists.

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

Psychotic reactions.

Psychotic reactions have been reported in patients receiving quinolones, including levofloxacin. In very rare cases, these progressed to suicidal thoughts and self-destructive behavior, sometimes after a single dose of levofloxacin (see section "Adverse reactions"). If such reactions occur, levofloxacin should be discontinued and appropriate measures taken. Alternative non-fluoroquinolone antibacterial therapy should be considered. Levofloxacin should be used with caution in patients with psychotic disorders or a history of psychiatric illness.

QT interval prolongation.

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

• congenital 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 younger women may be more sensitive to medicinal products that prolong the QT interval; therefore, caution is required when using fluoroquinolones, including levofloxacin, in these patient groups (see sections "Interaction with other medicinal products and other forms of interaction", "Dosage and administration", "Overdose", and "Adverse reactions").

Peripheral neuropathy.

Cases of sensory or sensorimotor polyneuropathy, leading to paresthesia, hyposthesia, dysesthesia, or weakness, have been reported in patients receiving quinolones or fluoroquinolones. Patients receiving levofloxacin should be advised to inform their physician if they develop symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness, before continuing treatment, to prevent potentially irreversible conditions (see section "Adverse reactions").

Hepatobiliary disorders.

Cases of necrotizing hepatitis up to fatal hepatic failure have been reported during treatment with levofloxacin, primarily in patients with severe underlying conditions such as sepsis (see section "Adverse reactions"). Patients should be advised to discontinue treatment and consult a physician if symptoms or 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 reported in the post-marketing period, including fatal cases and the need for respiratory support, have been associated with the use of fluoroquinolones in patients with myasthenia gravis. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances.

If any visual disturbances occur during treatment with levofloxacin, patients should seek immediate ophthalmological evaluation (see sections "Ability to influence reaction speed when driving or operating machinery" and "Adverse reactions").

Superinfection.

The use of levofloxacin, particularly prolonged use, may lead to the overgrowth of resistant microorganisms. If superinfection develops during therapy, appropriate measures should be taken.

Effect on laboratory test results.

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

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

Aortic aneurysm/dissection, valvular 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 (see section "Adverse reactions").

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

Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and consideration of alternative treatment options in patients with a history of aortic aneurysm or congenital heart valve defect, or in patients with existing aortic aneurysm and/or dissection or heart valve disease, as well as other risk factors or conditions predisposing to their development:

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

The risk of aortic aneurysm/dissection and rupture may be increased in patients concurrently taking corticosteroids.

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

Patients should be advised to seek immediate medical help if they experience acute dyspnea, new-onset palpitations, abdominal swelling, or lower limb edema.

Acute pancreatitis.

Acute pancreatitis may occur in patients taking levofloxacin. Patients should be informed about the characteristic symptoms of acute pancreatitis. Patients experiencing nausea, malaise, abdominal discomfort, severe abdominal pain, or vomiting should undergo immediate medical evaluation. Levofloxacin should be discontinued if acute pancreatitis is suspected. If confirmed, levofloxacin therapy should not be resumed. Caution is advised 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 treatment with levofloxacin (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 with regard to reproductive toxicity. However, due to the lack of human studies and experimental data indicating a risk of fluoroquinolone-induced damage to the weight-bearing cartilage of the growing organism, levofloxacin should not be administered to pregnant women (see section "Contraindications").

Breastfeeding period.

Levofloxacin is contraindicated in women who are 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 fluoroquinolone-induced damage to the weight-bearing cartilage of the growing organism, levofloxacin should not be administered to women who are breastfeeding (see section "Contraindications").

Fertility.

Levofloxacin has been shown not to impair fertility or reproductive function in rats.

Ability to influence reaction speed when driving or operating machinery.

Levofloxacin has a minor or moderate influence 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 drug should be taken 1 or 2 times daily. The dosage depends on the type and severity of infection, as well as the susceptibility of the likely pathogen.

The drug may also be used to complete the course of therapy in patients who have shown improvement during initial intravenous levofloxacin treatment; considering the bioequivalence of parenteral and oral forms, the same dosage may be applied.

Dosage. The following dosage recommendations may be provided for the drug:

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

Indications	Daily dose, mg (depending on severity)	Number of doses per day	Treatment duration (depending on severity)
Acute bacterial sinusitis	500	1 time	10-14 days
Exacerbation of chronic obstructive pulmonary disease, including bronchitis	500	1 time	7-10 days
Community-acquired pneumonia	500	1-2 times	7-14 days
Acute pyelonephritis	500	1 time	7-10 days
Complicated urinary tract infections	500	1 time	7-14 days
Uncomplicated cystitis	250*	1 time	3 days
Chronic bacterial prostatitis	500	1 time	28 days
Complicated skin and soft tissue infections	500	1-2 times	7-14 days
Pulmonary form of anthrax	500	1 time	8 weeks

*Since the tablet is not scored, when prescribing the drug at a dose of 250 mg or less, levofloxacin formulations allowing such dosage should be used.

Special populations

Dosing for patients with renal impairment (creatinine clearance ≤50 mL/min).

Creatinine clearance, mL/min	Dosing regimen
	250* mg/24 hours	500 mg/24 hours	500 mg/12 hours
50-20	first dose: 250* mg	first dose: 500 mg	first dose: 500 mg
	subsequent: 125* mg/24 hours	subsequent: 250* mg/24 hours	subsequent: 250* mg/12 hours
19-10	first dose: 250* mg	first dose: 500 mg	first dose: 500 mg
	subsequent: 125* mg/48 hours	subsequent: 125* mg/24 hours	subsequent: 125* mg/12 hours
10 (including hemodialysis and CAPD 1)	first dose: 250* mg	first dose: 500 mg	first dose: 500 mg
	subsequent: 125* mg/48 hours	subsequent: 125* mg/24 hours	subsequent: 125* mg/24 hours

*Since the tablet is not scored, when prescribing the drug at a dose of 250 mg or less, levofloxacin formulations allowing such dosing should be used.

1Additional doses are not required after hemodialysis or chronic ambulatory peritoneal dialysis (CAPD).

Hepatic impairment. Dose adjustment is not necessary, as levofloxacin is minimally metabolized in the liver and is primarily excreted via the kidneys.

Elderly patients. If renal function is normal, dose adjustment is not required (see section "Special precautions for use").

Children. The drug is contraindicated in children under 18 years of age (see section "Contraindications").

Method of administration. Tablets should be swallowed whole with sufficient fluid. Tablets may be taken during or between meals. The drug should be administered at least 2 hours before or after administration of iron salts, zinc salts, antacids containing magnesium or aluminum, or didanosine (only for didanosine formulations containing aluminum or magnesium buffering agents) and sucralfate, as reduced absorption may occur (see section "Interaction with other medicinal products and other forms of interaction").

Children.

The drug is contraindicated in children under 18 years of age (see section "Contraindications").

Overdose.

Symptoms. The most important signs expected after acute levofloxacin overdose include central nervous system symptoms such as confusion, myoclonus, hallucinations, tremor, dizziness, impaired consciousness, and seizures, QT interval prolongation, as well as gastrointestinal reactions such as nausea and mucosal erosions.

During post-marketing use of levofloxacin, central nervous system disturbances including confusion, convulsions, hallucinations, and tremor have been observed.

Treatment. In case of overdose, symptomatic treatment should be administered. ECG monitoring is required due to the potential for QT interval prolongation. Antacids may be used to protect gastric mucosa. Hemodialysis, including peritoneal dialysis and CAPD, is not effective in removing levofloxacin from the body. There are no specific antidotes.

Side effects

The adverse reactions listed below are categorized 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), and not known (frequency cannot be estimated from available data). Within each frequency group, adverse reactions are listed in decreasing order of severity.

Infections and infestations:
Uncommon – fungal infections, including Candida species, pathogen resistance.

Blood and lymphatic system disorders:
Uncommon – leukopenia, eosinophilia; rare – thrombocytopenia, neutropenia; not known – bone marrow failure, including aplastic anemia, pancytopenia, agranulocytosis, hemolytic anemia.

Immune system disorders:
Rare – angioneurotic edema, hypersensitivity (see section "Special precautions"); not known – anaphylactic shock*, anaphylactoid shock* (see section "Special precautions").

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

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

Psychiatric disorders***:
Common – insomnia; uncommon – anxiety, confusion, restlessness; rare – psychotic reactions (e.g., with hallucinations, paranoia), depression, agitation, unusual dreams, night terrors, delirium; 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; rare – seizures (see section "Contraindications" and "Special precautions"), paresthesia, memory impairment; not known – peripheral sensory neuropathy (see section "Special precautions"), peripheral sensorimotor neuropathy (see section "Special precautions"), parosmia including anosmia, dyskinesia, extrapyramidal disorders, ageusia, syncope, benign intracranial hypertension, myoclonus.

Eye disorders***:
Rare – visual disturbances such as blurred vision (see section "Special precautions"); not known – transient loss of vision (see section "Special precautions"), uveitis.

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

Cardiac disorders ****:
Rare – tachycardia, palpitations; not known – ventricular tachycardia that 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 electrocardiogram (see sections "Special precautions" and "Overdose").

Vascular disorders****:
Rare – arterial hypotension.

Respiratory system disorders:
Uncommon – dyspnea; not known – bronchospasm, allergic pneumonitis.

Gastrointestinal disorders:
Common – diarrhea, vomiting, nausea; uncommon – abdominal pain, dyspepsia, bloating, constipation; not known – hemorrhagic diarrhea, which may indicate enterocolitis, including pseudomembranous colitis (see section "Special precautions"), pancreatitis (see section "Special precautions").

Hepatobiliary disorders:
Common – increased liver enzymes (ALT/AST, alkaline phosphatase, GGT); uncommon – increased blood bilirubin levels; not known – jaundice and severe hepatic injury, including cases of fatal acute liver failure, mainly in patients with severe underlying conditions (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) (see section "Special precautions"), persistent drug eruption; not known – toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, erythema multiforme, photosensitivity reactions (see section "Special precautions"), leukocytoclastic vasculitis, stomatitis, skin hyperpigmentation.

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

Renal and urinary disorders:
Uncommon – increased serum creatinine levels; rare – acute renal failure (e.g., due to interstitial nephritis).

General disorders***:
Uncommon – asthenia; rare – pyrexia; not known – pain (including back, chest, and limb pain).

Other adverse reactions associated with fluoroquinolone use include:

• Acute attacks of porphyria in patients with porphyria.

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

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

*** Rare, prolonged (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting one or multiple organ systems or sensory organs have been reported in patients receiving quinolones and fluoroquinolones, sometimes in the absence of risk factors (see section "Special precautions"). These include tendonitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathy associated with paresthesia, neuralgia, fatigue, psychiatric symptoms (which may include, but are not limited to, sleep disorders, anxiety, panic attacks, depression, and suicidal thoughts), memory and concentration impairment, confusion, hearing, vision, taste, and smell disturbances.

**** Cases of aneurysm and aortic dissection, sometimes complicated by rupture (including fatal cases), and valvular regurgitation or 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 drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.
Keep out of reach and sight of children.

Packaging.

5 or 10 tablets in a blister; 1 blister per cardboard package.

Prescription status.

Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of operations.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.

INSTRUCTIONS

for medical use of the medicinal product

TAIGERON®

(TIGERON®)

Composition:

Active substance: levofloxacin (levofloxacin);

1 tablet contains levofloxacin hemihydrate equivalent to levofloxacin 500 mg or 750 mg;

Excipients: povidone K29/32, microcrystalline cellulose, crospovidone, magnesium stearate, colloidal anhydrous silicon dioxide, Opadry 03B84681 pink coating: hypromellose, titanium dioxide (E 171), polyethylene glycols, iron oxide red (E 172), iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: capsule-shaped, film-coated tablets, pink in colour, with "500" or "750" embossed 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 and is the S(-) enantiomer of the racemic mixture of the drug ofloxacin.

Mechanism of action.

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

Pharmacokinetic/pharmacodynamic relationship.

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

Mechanism of resistance.

Resistance to levofloxacin develops through a stepwise mutation process of the target site in both types of topoisomerase II, DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as reduced permeability (common in Pseudomonas aeruginosa) and efflux mechanisms, may also affect susceptibility to levofloxacin.

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

Clinical breakpoints.

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

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

Pathogen	Susceptible	Resistant
Enterobacteriaceae	≤0.5 mg/L	>1 mg/L
Pseudomonas spp.	≤0.001 mg/L	>1 mg/L
Acinetobacter spp.	≤0.5 mg/L	>1 mg/L
Staphylococcus aureus Coagulase-negative staphylococci	≤0.001 mg/L	>1 mg/L
Enterococcus spp.1	≤4 mg/L	>4 mg/L
Streptococcus pneumoniae	≤0.001 mg/L	>2 mg/L
Streptococcus A, B, C, G	≤0.001 mg/L	>2 mg/L
Haemophilus influenzae	≤0.06 mg/L	>0.06 mg/L
Moraxella catarrhalis	≤0.125 mg/L	>0.125 mg/L
Helicobacter pylori	≤1 mg/L	>1 mg/L
Aerococcus sanguinicola and urinae 2	≤2 mg/L	>2 mg/L
Aeromonas spp.	≤0.5 mg/L	>1 mg/L
Pharmacokinetic/pharmacodynamic (non-species-related) breakpoints	≤0.5 mg/L	>1 mg/L
1 Only uncomplicated urinary tract infections. 2 Inference on susceptibility can be based on susceptibility to ciprofloxacin.

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

Usually susceptible species Aerobic gram-positive bacteria: Bacillus anthracis, Staphylococcus aureus methicillin-susceptible, Staphylococcus saprophyticus, Streptococci group C and G, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes. Aerobic gram-negative bacteria: Eikenella corrodens, Haemophilus influenzae, Haemophilus para-influenzae, Klebsiella oxytoca, Moraxella catarrhalis, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri. Anaerobic bacteria: Peptostreptococcus. Others: Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamydia trachomatis, Legionella pneumophila, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum. Species for which acquired resistance may be a problem Aerobic gram-positive bacteria: Enterococcus faecalis, Staphylococcus aureus methicillin-resistant*, coagulase-negative Staphylococcus spp. Aerobic gram-negative bacteria: Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens. Anaerobic bacteria: Bacteroides fragilis. Naturally resistant strains Aerobic gram-positive bacteria: Enterococcus faecium.

*Methicillin-resistant S. aureus is highly likely to exhibit co-resistance to fluoroquinolones, including levofloxacin.

Pharmacokinetics.

Absorption.

Orally administered levofloxacin is rapidly and almost completely absorbed; Cmax is reached within 1–2 hours. Absolute bioavailability is 99–100%.

Food has minimal effect on the absorption of levofloxacin.

Steady-state concentrations are achieved within 48 hours with dosing regimens of 500 mg once or twice daily.

Distribution.

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

Penetration into tissues and body fluids.

Penetration of levofloxacin has been demonstrated into bronchial mucosa, bronchial secretions, lung tissue, alveolar macrophages, skin (vesicular fluid), prostate tissue, and urine. However, levofloxacin penetrates poorly into cerebrospinal fluid.

Biotransformation.

Levofloxacin undergoes minimal metabolism, with metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for < 5% of the administered dose and are excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.

Elimination.

Following both oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life (t1/2) is 6–8 hours). It is primarily excreted by the kidneys (>85% of the administered dose). Mean 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 interchangeability of these routes.

Linearity.

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

Patients with renal impairment.

The pharmacokinetics of levofloxacin are affected by the degree of renal function impairment. With declining renal function, renal excretion and clearance decrease, and t1/2 increases, as shown in the table below.

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

Creatinine clearance (ml/min)	<20	20-49	50-80
Renal clearance (ml/min)	13	26	57
t1/2 (hours)	35	27	9

Geriatric patients.

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

Gender differences.

Separate analysis of male and female 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.

The drug is indicated in adults for the treatment of the following infections (see sections "Pharmacodynamics" and "Special instructions"):

• Acute pyelonephritis and complicated urinary tract infections (see section "Special instructions").
• Chronic bacterial prostatitis.
• Pulmonary form of anthrax: post-exposure prophylaxis and treatment (see section "Special instructions").

The drug should be used for the following infections only when it is considered inappropriate to use antibacterial agents usually recommended for initial treatment of these infections:

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

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

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

Contraindications.

Hypersensitivity to levofloxacin, other quinolones, or to any excipients of the drug.

Epilepsy.

History of tendon disorders related to fluoroquinolone administration.

Age under 18 years.

Pregnancy and breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on levofloxacin

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

Absorption of levofloxacin is significantly reduced when administered simultaneously with iron salts or antacids containing magnesium or aluminium, or didanosine (only for formulations containing aluminium or magnesium buffering agents). Concurrent administration of fluoroquinolones with multivitamins containing zinc leads to reduced oral absorption. It is not recommended to take products containing divalent or trivalent cations, such as iron salts, zinc salts, antacids containing magnesium or aluminium, or didanosine (only for didanosine formulations containing aluminium or magnesium buffering agents), within 2 hours before/after administration of levofloxacin (see section "Dosage and administration"). Calcium salts had minimal effect on the oral absorption of levofloxacin.

Sucralfate.

Bioavailability of levofloxacin is significantly reduced when administered concomitantly with sucralfate. If a patient needs to receive both sucralfate and levofloxacin, it is preferable to take sucralfate 2 hours after levofloxacin (see section "Special instructions").

Theophylline, fenbufen or similar non-steroidal anti-inflammatory drugs.

No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant reduction in seizure threshold may occur when quinolones are administered concomitantly with theophylline, non-steroidal anti-inflammatory drugs, and other agents that reduce seizure threshold. Levofloxacin concentration in the presence of fenbufen was approximately 13% higher than when levofloxacin was administered alone.

Probenecid and cimetidine.

Probenecid and cimetidine statistically significantly affect the elimination of levofloxacin. Renal clearance of levofloxacin is reduced by cimetidine (24%) and probenecid (34%). This occurs because both drugs can block tubular secretion of levofloxacin. Despite this, statistically significant kinetic differences are unlikely to have clinical significance. Levofloxacin should be prescribed with caution concomitantly with drugs affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other significant information.

It is known that no clinically significant effect on the pharmacokinetics of levofloxacin occurs when administered together with calcium carbonate, digoxin, glyburide, or ranitidine.

Effect of levofloxacin on other medicinal products

Cyclosporine.

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

Vitamin K antagonists.

When administered concomitantly with vitamin K antagonists (e.g., warfarin), increased values of coagulation tests (INR/PT) and/or bleeding, which may be severe, have been reported. Therefore, patients receiving vitamin K antagonists concomitantly should be monitored for coagulation parameters (see section "Special instructions").

Medicinal products that prolong 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 instructions").

Other significant information. 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.

Other forms of interaction

Food.

No clinically significant interaction with food has been observed. Therefore, the drug can be administered independently of food intake.

Special precautions for use.

Levofloxacin should be avoided in patients with a history of serious adverse reactions to drugs containing quinolones or fluoroquinolones (see section "Adverse reactions"). Treatment with levofloxacin in such patients should only be initiated if no alternative treatment options are available and after careful assessment of the benefit-risk ratio (see section "Contraindications").

Staphylococcus aureus resistant to methicillin.

For methicillin-resistant Staphylococcus aureus (MRSA), there is a very high likelihood of co-resistance to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of infections known or suspected to be caused by MRSA, except when laboratory testing has confirmed susceptibility of the pathogen to levofloxacin.

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

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

Pulmonary anthrax.

The use of the drug for treatment in humans is based on in vitro data on susceptibility of Bacillus anthracis, experimental animal data, and limited human treatment data. Physicians should refer to national and/or international consensus treatment guidelines for anthrax.

Prolonged, disabling, and potentially irreversible serious adverse reactions.

Rare cases of prolonged (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting one or more body systems (musculoskeletal, nervous, psychiatric systems, and sensory organs) have been reported in patients receiving quinolones or fluoroquinolones, regardless of age or presence of risk factors. If any signs or symptoms of a serious adverse reaction occur, levofloxacin should be discontinued immediately and medical advice should be sought.

Tendinitis and tendon rupture.

Tendinitis and tendon ruptures (particularly of the Achilles tendon, but not exclusively) may occur within 48 hours of starting quinolone or fluoroquinolone therapy or even several months after discontinuation of therapy. Patients of advanced age, those with impaired renal function or organ transplants, patients receiving more than 1000 mg of levofloxacin per day, and those taking corticosteroids are at higher risk of developing tendinitis and tendon ruptures. Therefore, concomitant use of corticosteroids with levofloxacin should be avoided.

If early signs of tendinitis (e.g., inflammation and swelling accompanied by pain) occur, levofloxacin 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 treated with levofloxacin (see section "Adverse reactions"). The risk of myoclonus is increased in elderly patients and in patients with renal impairment if the levofloxacin dose has not been 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 treatment with the drug (including several weeks after treatment) may be a symptom of Clostridium difficile-associated disease (CDAD). CDAD may range in severity from mild to life-threatening; the most severe form is pseudomembranous colitis (see section "Adverse reactions"). It is therefore important to consider this diagnosis in patients who develop severe diarrhea during or after treatment with levofloxacin. If CDAD is suspected or confirmed, the drug should be discontinued immediately and appropriate therapy initiated without delay. Antiperistaltic agents 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 (see section "Contraindications") and, as with other quinolones, should be used with extreme caution in patients predisposed to seizures or when used concomitantly with substances 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"), levofloxacin treatment should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency.

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

Patients with renal impairment.

Since levofloxacin is primarily excreted via the kidneys, the dose should be adjusted in patients with impaired renal function (see section "Posology and method of administration").

Hypersensitivity reactions.

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

Severe skin reactions.

Severe skin reactions, which may be life-threatening or fatal, including toxic epidermal necrolysis (TEN, also known as Lyell's syndrome), Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported during levofloxacin use (see section "Adverse reactions"). Patients should be informed about the signs and symptoms of severe skin reactions and monitored closely. If signs or symptoms suggestive of these reactions occur, levofloxacin treatment should be discontinued immediately and alternative therapy considered. If a patient develops one of these serious adverse reactions (e.g., SJS, TEN, or DRESS syndrome) during levofloxacin treatment, reinitiation of levofloxacin therapy is absolutely contraindicated.

Alteration of blood glucose levels.

Alterations in blood glucose levels (including both hyperglycemia and hypoglycemia) have been reported with quinolone use, particularly in patients with diabetes mellitus who are concurrently taking oral hypoglycemic agents (e.g., glyburide) or insulin. Cases of hypoglycemic coma have been documented. Blood glucose levels should be monitored in diabetic patients (see section "Adverse reactions"). If a patient reports disturbances in blood glucose levels, levofloxacin treatment should be discontinued immediately and alternative antibacterial therapy considered.

Prevention of photosensitization.

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

Patients receiving vitamin K antagonists.

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

Psychotic reactions.

Psychotic reactions have been observed in patients taking quinolones, including levofloxacin. In very rare cases, these progressed to suicidal thoughts and self-destructive behavior, sometimes after only a single dose of levofloxacin (see section "Adverse reactions"). If such reactions occur, levofloxacin should be discontinued and appropriate measures taken. Alternative non-fluoroquinolone antibacterial therapy should be considered. Levofloxacin should be used with caution in patients with psychotic disorders or a history of psychiatric illness.

QT interval prolongation.

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

• congenital 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);
• cardiac disease (e.g., heart failure, myocardial infarction, bradycardia).

Elderly patients and younger 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 sections "Interaction with other medicinal products and other forms of interaction", "Posology and method of administration", "Overdose", and "Adverse reactions").

Peripheral neuropathy.

Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones or fluoroquinolones. Patients taking levofloxacin should be advised to inform their physician about the development of neuropathy symptoms—such as pain, burning, tingling, numbness, or weakness—before continuing treatment, to prevent potentially irreversible conditions (see section "Adverse reactions").

Hepatobiliary disorders.

Cases of necrotic hepatitis up to fatal hepatic failure have been reported with levofloxacin use, primarily in patients with severe underlying conditions such as sepsis (see section "Adverse reactions"). Patients should be advised to discontinue treatment and seek medical advice if symptoms 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 fatal cases and the need for respiratory support, have been reported in the post-marketing period in patients with myasthenia gravis treated with fluoroquinolones. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances.

If any visual disturbances occur during levofloxacin treatment, patients should seek immediate ophthalmological consultation (see sections "Effect on ability to drive and use machines" and "Adverse reactions").

Superinfection.

The use of levofloxacin, particularly prolonged use, may lead to the overgrowth of resistant microorganisms. If superinfection develops during therapy, appropriate measures should be taken.

Effect on laboratory test results.

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

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

Aortic aneurysm/dissection, valvular regurgitation/insufficiency.

Epidemiological studies have reported an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and aortic and mitral valve regurgitation following fluoroquinolone use (see section "Adverse reactions").

Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and valvular regurgitation/insufficiency have been reported in patients receiving fluoroquinolones (see section "Adverse reactions").

Therefore, fluoroquinolones should only be used after careful assessment of the benefit-risk ratio and consideration of alternative treatment options in patients with a history of aortic aneurysm or congenital heart valve defects, or in patients with existing aortic aneurysm and/or dissection or heart valve disease, as well as in patients with other risk factors or conditions predisposing to their development:

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

The risk of aortic aneurysm/dissection and rupture may be increased in patients concurrently taking corticosteroids.

If sudden abdominal, chest, or back pain occurs, patients should seek immediate emergency medical help.

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

Acute pancreatitis.

Acute pancreatitis may occur in patients taking levofloxacin. Patients should be informed about the typical symptoms of acute pancreatitis. Patients experiencing nausea, malaise, abdominal discomfort, severe abdominal pain, or vomiting should undergo immediate medical evaluation. If acute pancreatitis is suspected, levofloxacin should be discontinued. If confirmed, levofloxacin treatment should not be resumed. Caution is advised in patients with a history of pancreatitis (see section "Adverse reactions").

Blood disorders.

During treatment with levofloxacin, bone marrow suppression may develop, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, or agranulocytosis (see section "Adverse reactions"). If any of these disorders are suspected, blood test results should be monitored. If abnormal results are obtained, discontinuation of levofloxacin treatment 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 with regard to reproductive toxicity. However, due to the lack of human studies and experimental data indicating a risk of fluoroquinolone-induced damage to the weight-bearing joint cartilage of the growing organism, levofloxacin should not be administered to pregnant women (see section "Contraindications").

Breastfeeding.

Levofloxacin is contraindicated in women who are 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 fluoroquinolone-induced damage to the weight-bearing joint cartilage of the growing organism, levofloxacin should not be administered to women who are breastfeeding (see section "Contraindications").

Fertility.

Levofloxacin has been shown not to impair fertility or reproductive function in rats.

Effect on ability to drive and use machines.

Levofloxacin has a negligible or moderate effect on the ability to drive vehicles or operate machinery. Some adverse reactions (e.g., dizziness/vertigo, somnolence, visual disturbances) may impair a patient's concentration 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 drug should be taken once or twice daily. The dose depends on the type and severity of infection and the susceptibility of the likely pathogen.

The drug may also be used to complete a course of therapy in patients who have shown improvement during initial intravenous levofloxacin treatment; considering the bioequivalence of parenteral and oral forms, the same dosage may be used.

Dosage. The following dosage recommendations may be provided for the drug:

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

Indications	Daily dose, mg (depending on severity)	Number of doses per day	Treatment duration (depending on severity)
Acute bacterial sinusitis	500	1 time	10-14 days
Exacerbation of chronic obstructive pulmonary disease, including bronchitis	500	1 time	7-10 days
Community-acquired pneumonia	500	1-2 times	7-14 days
Acute pyelonephritis	500	1 time	7-10 days
Complicated urinary tract infections	500	1 time	7-14 days
Uncomplicated cystitis	250*	1 time	3 days
Chronic bacterial prostatitis	500	1 time	28 days
Complicated skin and soft tissue infections	500	1-2 times	7-14 days
Pulmonary form of anthrax	500	1 time	8 weeks

*Since the tablet is not scored, when prescribing the drug at a dose of 250 mg or less, levofloxacin formulations allowing such dosing should be used.

Special populations

Dosing for patients with renal impairment (creatinine clearance ≤50 mL/min).

Creatinine clearance, mL/min	Dosing regimen
	250* mg/24 hours	500 mg/24 hours	500 mg/12 hours
50–20	initial dose: 250* mg	initial dose: 500 mg	initial dose: 500 mg
	subsequent: 125* mg/24 hours	subsequent: 250* mg/24 hours	subsequent: 250* mg/12 hours
19–10	initial dose: 250* mg	initial dose: 500 mg	initial dose: 500 mg
	subsequent: 125* mg/48 hours	subsequent: 125* mg/24 hours	subsequent: 125* mg/12 hours
<10 (including hemodialysis and CAPD1)	initial dose: 250* mg	initial dose: 500 mg	initial dose: 500 mg
	subsequent: 125* mg/48 hours	subsequent: 125* mg/24 hours	subsequent: 125* mg/24 hours

*Since the tablet is not divisible, when prescribing the drug at a dose of 250 mg or less, levofloxacin formulations allowing such dosing should be used.

1Additional doses are not required after hemodialysis or continuous ambulatory peritoneal dialysis (CAPD).

Hepatic impairment. Dose adjustment is not necessary, as levofloxacin is minimally metabolized in the liver and is primarily excreted via the kidneys.

Elderly patients. If renal function is not impaired, dose adjustment is not required (see section "Special precautions for use").

Children. The drug is contraindicated in children under 18 years of age (see section "Contraindications").

Administration method. Tablets should be swallowed whole with sufficient fluid. Tablets may be taken during or between meals. The drug should be administered at least 2 hours before or after administration of iron salts, zinc salts, antacids containing magnesium or aluminum, or didanosine (only for didanosine formulations containing aluminum or magnesium buffering agents) and sucralfate, as reduced absorption may occur (see section "Interaction with other medicinal products and other forms of interaction").

Children.

The drug is contraindicated in children under 18 years of age (see section "Contraindications").

Overdose.

Symptoms. The most important signs expected after acute levofloxacin overdose include central nervous system symptoms such as confusion, myoclonus, hallucinations, tremor, dizziness, impaired consciousness, and seizures, QT interval prolongation, as well as gastrointestinal reactions such as nausea and mucosal erosions.

During post-marketing use of levofloxacin, central nervous system disturbances have been observed, including confusion, convulsions, hallucinations, and tremor.

Treatment. In case of overdose, symptomatic treatment should be administered. ECG monitoring is necessary due to the potential for QT interval prolongation. Antacids may be used to protect the gastric mucosa. Hemodialysis, including peritoneal dialysis and CAPD, is not effective in removing levofloxacin from the body. There are no specific antidotes.

Side effects

The adverse reactions listed below are categorized 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), and not known (frequency cannot be estimated from available data). Within each frequency group, adverse events are listed in order of decreasing severity.

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

Blood and lymphatic system disorders:

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

Immune system disorders: rare – angioedema, hypersensitivity (see section "Special precautions for use"); not known – anaphylactic shock*, anaphylactoid shock* (see section "Special precautions for use").

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

Metabolism and nutrition disorders: uncommon – anorexia; rare – hypoglycemia, mainly in patients with diabetes, hypoglycemic coma (see section "Special precautions for use"); not known – hyperglycemia (see section "Special precautions for use").

Psychiatric disorders***: common – insomnia; uncommon – anxiety, confusion, restlessness; rare – psychotic reactions (e.g., with hallucinations, paranoia), depression, agitation, unusual dreams, nightmares, delirium; not known – 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 section "Contraindications" and "Special precautions for use"), paresthesia, memory impairment; not known – peripheral sensory neuropathy (see section "Special precautions for use"), peripheral sensorimotor neuropathy (see section "Special precautions for use"), parosmia, including anosmia, dyskinesia, extrapyramidal disorders, ageusia, syncope, benign intracranial hypertension, myoclonus.

Eye disorders***: rare – visual disturbances, such as blurred vision (see section "Special precautions for use"); not known – transient loss of vision (see section "Special precautions for use"), uveitis.

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

Cardiac disorders ****: rare – tachycardia, palpitations; not known – ventricular tachycardia that 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 electrocardiogram (see sections "Special precautions for use" and "Overdose").

Vascular disorders****: rare – arterial hypotension.

Respiratory system disorders: uncommon – dyspnea; not known – bronchospasm, allergic pneumonitis.

Gastrointestinal disorders: common – diarrhea, vomiting, nausea; uncommon – abdominal pain, dyspepsia, bloating, constipation; 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 liver enzyme levels (ALT/AST, alkaline phosphatase, GGT); uncommon – increased blood bilirubin levels; not known – jaundice and severe liver injury, including cases of fatal acute liver failure, 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 reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special precautions for use"), persistent drug eruption; 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 tendinitis (e.g., Achilles tendon); muscle weakness, which may be particularly significant in patients with myasthenia gravis (see section "Special precautions for use"); not known – rhabdomyolysis, tendon rupture (e.g., Achilles tendon; see section "Special precautions for use"), ligament rupture, muscle rupture, arthritis.

Renal and urinary disorders: uncommon – increased serum creatinine levels; rare – acute renal failure (e.g., due to interstitial nephritis).

General disorders***: uncommon – asthenia; rare – pyrexia; not known – pain (including back, chest, and limb pain).

Other adverse reactions associated with fluoroquinolone use include:

• Acute attacks of porphyria in patients with porphyria.

* 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.

*** Rare, prolonged (lasting months or years), disabling, and potentially irreversible serious adverse reactions affecting various, sometimes multiple organ systems or sensory organs have been reported in patients treated with quinolones and fluoroquinolones, in some cases without risk factors (see section "Special precautions for use"). These include tendonitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathy associated with paresthesia, neuralgia, fatigue, psychiatric symptoms (which may include, but are not limited to, sleep disorders, anxiety, panic attacks, depression, and suicidal thoughts), memory and attention disturbances, confusion, hearing, vision, taste, and smell disorders.

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

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 and patients, or 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. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

5 or 10 tablets in a blister; 1 blister per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

LLC "GLEDFARM LTD".

Manufacturer's address and location of business activity.

54 Davydovskoho Hryhorii Street, Sumy, Sumy region, 40020, Ukraine.