Targetry

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Targetri

Composition:

Active substance: levofloxacin;

One film-coated tablet contains levofloxacin (as levofloxacin hemihydrate) 250 mg;

Excipients: microcrystalline cellulose, hydroxypropylcellulose, crospovidone, magnesium stearate; film coating: hypromellose, indigocarmine aluminum lake (E 132), "Sunset Yellow" aluminum lake (E 110), red iron oxide (E 172), macrogol 4000, titanium dioxide (E 171).

One film-coated tablet contains levofloxacin (as levofloxacin hemihydrate) 500 mg;

Excipients: microcrystalline cellulose, hydroxypropylcellulose, crospovidone, magnesium stearate; film coating: hypromellose, indigocarmine aluminum lake (E 132), "Sunset Yellow" aluminum lake (E 110), red iron oxide (E 172), macrogol 4000, titanium dioxide (E 171), yellow iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Film-coated tablets, 250 mg: pink, oval, biconvex tablets with a score line, sized: 13.7 mm ± 0.1 mm, 6.7 mm ± 0.1 mm, and thickness 3.8 mm ± 0.2 mm;

Film-coated tablets, 500 mg: orange, oval, biconvex tablets with a score line, sized: 19.3 mm ± 0.1 mm, 7.8 mm ± 0.1 mm, and thickness 5.0 mm ± 0.2 mm.

Pharmacotherapeutic group. Antibacterial agents of the quinolone group. Fluoroquinolones.

ATC code J01MA12.

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

Mechanism of resistance. Resistance to levofloxacin develops through a stepwise process of mutations in the target sites of 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.

Breakpoints. The EUCAST recommended MIC breakpoints for levofloxacin, which distinguish susceptible microorganisms from intermediate (moderately resistant) organisms, and intermediate from resistant organisms, are presented in the table below.

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

Pathogen	Susceptible	Resistant
Enterobacterales	≤ 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	≤ 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 and 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 urinae2	≤ 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 Susceptibility can be determined based on susceptibility to ciprofloxacin.

The prevalence of resistance may vary geographically and over time for individual species, and information on local microbial resistance should be sought, especially when treating severe infections. When necessary, advice from a specialist should be obtained if local resistance prevalence renders the benefit of the medicinal product at least questionable for certain types of infections.

Typically susceptible species Aerobic gram-positive bacteria: Bacillus anthracis, Staphylococcus aureus methicillin-susceptible, Staphylococcus saprophyticus, Streptococci groups C and G, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes. Aerobic gram-negative bacteria: 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 capable of developing resistance Aerobic gram-positive bacteria: Enterococcus faecalis, Staphylococcus aureus methicillin-resistant*, coagulase-negative Staphylococcus spp. Aerobic gram-negative bacteria: Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens Anaerobic bacteria: Bacteroides fragilis. Naturally resistant strains Aerobic gram-positive bacteria: Enterococcus faecium.

*Methicillin-resistant S. aureus is highly likely to also be resistant to fluoroquinolones, including levofloxacin.

Pharmacokinetics

Absorption. When administered orally, levofloxacin is rapidly and almost completely absorbed; peak plasma concentrations 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 serum proteins. The mean volume of distribution of levofloxacin is approximately 100 L after single and repeated 500 mg doses, indicating extensive tissue distribution throughout the body.

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

Biotransformation. 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 (t½) is 6–8 hours). It is primarily excreted by the kidneys (> 85% of the administered dose).

Mean total systemic 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 dose range of 50 to 1000 mg.

Special patient populations

Patients with renal impairment. The pharmacokinetics of levofloxacin are affected by the degree of renal function impairment. With declining renal function, renal elimination and clearance decrease, and elimination half-life 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
Half-life (hours)	35	27	9

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

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

Clinical characteristics

Indications

Targret should be used in adults for the treatment of the following infections:

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

For the above-mentioned infections, the medicinal product should be used only when it is considered inappropriate to use antibacterial agents usually recommended for initial treatment of these infections.

• Acute bacterial sinusitis.
• Exacerbation of chronic obstructive pulmonary diseases, including bronchitis.
• Community-acquired pneumonia.
• Complicated skin and soft tissue infections.
• Uncomplicated cystitis (see section "Special precautions for use").

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

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

Contraindications

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

Epilepsy.

Tendon damage associated with fluoroquinolone use in medical history.

Childhood.

Pregnancy and breastfeeding.

Interaction with other medicinal products and other forms of interaction

Effects 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 didanosine (only 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 formulations of didanosine containing aluminium or magnesium buffering agents), within 2 hours before/after administration of levofloxacin. Calcium salts had minimal effect on the oral absorption of levofloxacin (see section "Dosage and administration").

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 administration (see section "Dosage and administration").

Theophylline, fenbufen, or similar nonsteroidal anti-inflammatory drugs (NSAIDs). No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant reduction in seizure threshold may occur with concomitant administration of quinolones with theophylline, nonsteroidal anti-inflammatory drugs, and other agents that reduce seizure threshold. The concentration of levofloxacin in the presence of fenbufen was approximately 13% higher than when levofloxacin was administered alone.

Probenecid and cimetidine statistically significantly affect the elimination of levofloxacin. Renal clearance of levofloxacin is reduced in the presence of cimetidine (by 24%) and probenecid (by 34%). This occurs because both drugs are capable of blocking 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 medicinal products. Clinical pharmacological studies have shown that calcium carbonate, digoxin, glyburide, and ranitidine have no clinically significant effect on the pharmacokinetics of levofloxacin.

Effects 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 in coagulation tests (prothrombin time [PT]/international normalized ratio [INR]) and/or bleeding, which may be severe, have been reported. Therefore, coagulation parameters should be monitored in patients receiving vitamin K antagonists concomitantly (see section "Special precautions for use").

Medicinal products that prolong the QT interval. Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, and antipsychotics) (see section "Special precautions for use. QT interval prolongation").

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

Other forms of interaction

Corticosteroids. The risk of tendinitis and tendon rupture is increased in patients receiving concomitant corticosteroid and levofloxacin therapy. Therefore, concomitant administration of corticosteroids and levofloxacin should be avoided.

Food intake. No clinically significant interaction with food has been observed. Therefore, the medicinal product can be taken independently of food intake.

Special precautions for use.

Levofloxacin should be avoided in patients who have previously experienced serious adverse reactions to drugs containing quinolone or fluoroquinolone (see section "Adverse reactions").

Treatment with levofloxacin in these patients should be initiated only if no alternative treatment options are available and after careful assessment of the benefit-risk ratio (see also section "Contraindications").

Risk of resistance development

For methicillin-resistant Staphylococcus aureus (MRSA), there is a very high probability 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 in cases where 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. When prescribing fluoroquinolones, local prevalence of fluoroquinolone resistance in Escherichia coli should be taken into account.

Use for the treatment of pulmonary anthrax is based on in vitro susceptibility data for Bacillus anthracis, animal studies, and limited human data. Physicians should follow national and/or international guidelines for the treatment of anthrax.

Prolonged, disabling, and potentially irreversible serious adverse reactions. In patients receiving quinolones and fluoroquinolones, very rare cases of prolonged (months or years), disabling, and potentially irreversible serious adverse reactions affecting various body systems (musculoskeletal, nervous system, psychiatric, and sensory organs) have been reported, regardless of age or presence of risk factors. Levofloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.

Tendinitis and tendon rupture. Tendinitis and tendon rupture (sometimes bilateral), particularly of the Achilles tendon, may occur within 48 hours of starting treatment with quinolones or fluoroquinolones and, as reported, even several months after discontinuation of therapy. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, organ transplant recipients, patients receiving a daily dose of 1000 mg levofloxacin, and those concurrently taking corticosteroids. Therefore, concomitant use of corticosteroids should be avoided. At the first signs of tendinitis (e.g., painful swelling, inflammation), levofloxacin should be discontinued and alternative therapy considered. Appropriate management of the affected limb (e.g., immobilization) is required. 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 levofloxacin dose is not adjusted according to creatinine clearance. If myoclonus occurs, levofloxacin should be discontinued immediately and appropriate treatment initiated.

Clostridium difficile-associated disease. Diarrhea, particularly severe, persistent, and/or hemorrhagic, during or after treatment (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, like other quinolones, should be used with extreme caution in patients predisposed to seizures or receiving concomitant medications that lower the cerebral seizure threshold, such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). In case of seizure episodes (see section "Adverse reactions"), treatment with levofloxacin should be discontinued.

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

Patients with renal impairment. Since levofloxacin is primarily excreted by the kidneys, dosage adjustment is required 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 adverse reactions. Serious skin adverse reactions, 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 and may be life-threatening or fatal (see section "Adverse reactions"). Patients should be informed about the signs and symptoms of severe skin reactions and monitored closely. If such symptoms occur, levofloxacin should be discontinued immediately and alternative therapy considered. If a patient develops a serious reaction such as SJS, TEN, or DRESS syndrome during levofloxacin treatment, re-initiation of levofloxacin therapy in this patient is absolutely contraindicated.

Disturbances in blood glucose. Alterations in blood glucose levels (including both hyperglycemia and hypoglycemia) have been reported with quinolone use, particularly in patients with diabetes mellitus receiving concomitant oral hypoglycemic agents (e.g., glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. Blood glucose levels should be monitored in diabetic patients (see section "Adverse reactions").

Treatment should be discontinued immediately if the patient reports disturbances in blood glucose levels, and alternative non-fluoroquinolone antibacterial therapy should be 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 sources (e.g., UV lamps, sunbeds) during treatment and for 48 hours after discontinuation of levofloxacin.

Patients receiving vitamin K antagonists. Increased coagulation test parameters (INR/aPTT) and/or bleeding may occur in patients taking levofloxacin concomitantly with a vitamin K antagonist (e.g., warfarin). Coagulation test parameters should therefore 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 reported in patients taking quinolones, including levofloxacin. In very rare cases, these progressed to suicidal thoughts and self-harming behavior, sometimes after only a single dose of levofloxacin (see section "Adverse reactions"). If such reactions occur, levofloxacin should be discontinued and appropriate measures taken. Caution is recommended when prescribing levofloxacin to patients with psychotic disorders or a history of psychiatric illness.

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

• congenital QT prolongation 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 imbalance (e.g., hypokalemia, hypomagnesemia);
• cardiac disease (e.g., heart failure, myocardial infarction, bradycardia).

Elderly patients and women may be more sensitive to drugs that prolong the QT interval; therefore, caution is required when using fluoroquinolones, including levofloxacin, in these populations (see sections "Posology and method of administration. Elderly patients", "Interaction with other medicinal products and other forms of interaction", "Adverse reactions", and "Overdose").

Peripheral neuropathies. Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and 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 the development of potentially irreversible conditions (see section "Adverse reactions").

Hepatobiliary disorders. Cases of necrotizing 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 consult a physician 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 associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances. If vision is impaired or any ocular effects occur, patients should seek immediate consultation with an ophthalmologist (see sections "Adverse reactions" and "Ability to affect reaction speed when driving or operating machinery").

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

Aneurysm and aortic dissection, and cardiac valve regurgitation/insufficiency. Data indicate 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").

Thus, fluoroquinolones should be used only after careful benefit-risk assessment and consideration of alternative therapies in patients with a family history of aneurysm or congenital heart valve defects, patients diagnosed with aortic aneurysm and/or aortic dissection, patients with heart valve disease, and in the presence of other risk factors, namely:

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

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

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

Patients should be advised to seek immediate medical help in case of acute dyspnea, new-onset palpitations, or development of abdominal or lower limb edema.

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, acute abdominal pain, or vomiting should undergo immediate medical evaluation. If acute pancreatitis is suspected, levofloxacin should be discontinued, and if confirmed, levofloxacin should not be restarted. Caution is recommended in patients with a history of pancreatitis.

Blood disorders. Bone marrow depression, 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.

Effect on laboratory test results. Urine opiate tests in patients taking levofloxacin may yield false-positive results. Confirmation of positive opiate test results using more specific methods may be necessary.

Levofloxacin inhibits the growth of Mycobacterium tuberculosis, so a false-negative result in bacteriological testing is possible in patients with tuberculosis.

Important information on excipients. Tartrazine (Yellow West), included in the formulation, may cause allergic reactions.

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. However, due to the lack of human data and because experimental evidence indicates a risk of cartilage damage in the growing organism by fluoroquinolones, levofloxacin should not be used during pregnancy (see section "Contraindications").

Breastfeeding

The medicinal product is contraindicated in women who are breastfeeding. There is insufficient information on the excretion of levofloxacin in breast milk; however, other fluoroquinolones are excreted in breast milk. Due to the lack of human data and because experimental evidence indicates a risk of cartilage damage in the growing organism by fluoroquinolones, levofloxacin should not be used in women who are breastfeeding (see section "Contraindications").

Fertility

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

Ability to affect reaction speed when driving or operating machinery

The medicinal product 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 medicinal product should be administered once or twice daily. The dose depends on the type and severity of the infection and the susceptibility of the likely pathogen.

The medicinal product may also be used to complete the course of therapy in patients who have shown improvement during initial intravenous administration of levofloxacin. Considering the bioequivalence of parenteral and oral formulations, the same dosage may be used.

Dosage

The recommended dosages of levofloxacin are provided below.

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

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

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

Creatinine clearance	Dosing regimen
	250 mg / 24 hours	500 mg / 24 hours	500 mg / 12 hours
	Initial dose: 250 mg	Initial dose: 500 mg	Initial dose: 500 mg
50–20 mL/min	Subsequent: 125 mg / 24 hours	Subsequent: 250 mg / 24 hours	Subsequent: 250 mg / 12 hours
19–10 mL/min	Subsequent: 125 mg / 48 hours	Subsequent: 125 mg / 24 hours	Subsequent: 125 mg / 12 hours
< 10 mL/min (including hemodialysis and CAPD) 1	Subsequent: 125 mg / 48 hours	Subsequent: 125 mg / 24 hours	Subsequent: 125 mg / 24 hours

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

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

Elderly patients. If renal function is not impaired, there is no need for dose adjustment (see section "Special precautions": "Tendinitis and tendon rupture", "QT interval prolongation").

Method of administration

Tablets should be swallowed whole with a sufficient amount of liquid. Tablets may be taken with or without food. The medicinal product should be administered at least 2 hours before or after administration of iron salts, zinc salts, antacids containing magnesium or aluminum, didanosine (only didanosine formulations containing aluminum or magnesium buffering agents), and sucralfate, as absorption may be reduced.

Children. The medicinal product is contraindicated in children (under 18 years of age) due to the potential risk of articular cartilage damage (see section "Contraindications").

Overdose

Based on animal toxicity studies and clinical pharmacology studies using doses higher than therapeutic doses, the most significant expected symptoms following acute levofloxacin overdose include central nervous system effects such as confusion, dizziness, altered 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 effects including confusion, seizures, myoclonus, hallucinations, and tremor have been reported.

In case of overdose, symptomatic treatment is recommended. ECG monitoring should be performed 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.

Adverse Reactions

The adverse reactions of levofloxacin are listed below by system organ class and frequency. Within each frequency group, adverse reactions are presented in order of decreasing severity of manifestations.

Organ systems	Common (from ≥ 1/100 to < 1/10)	Uncommon (from ≥ 1/1000 to < 1/100)	Rare (from ≥ 1/10000 to <1/1000)	Frequency unknown (cannot be estimated from available data)
Infections and infestations		Fungal infection, including infection caused by Candida species Resistance of pathogenic microorganisms
Blood and lymphatic system		Leukopenia Eosinophilia	Thrombocytopenia Neutropenia	Bone marrow failure, including aplastic anemia, pancytopenia, agranulocytosis, hemolytic anemia
Immune system			Angioedema Hypersensitivity (see section "Special warnings and precautions for use")	Anaphylactic shock Anaphylactoid shock (see section "Special warnings and precautions for use")
Metabolism and nutrition		Anorexia	Hypoglycemia, especially in patients with diabetes mellitus (see section "Special warnings and precautions for use") Hypoglycemic coma (see section "Special warnings and precautions for use")	Hypoglycemia (see section "Special warnings and precautions for use")
Endocrine system			Syndrome of inappropriate antidiuretic hormone secretion
Psychiatric*	Insomnia	Anxiety Confusion Nervousness	Psychotic reactions (e.g., with hallucinations, paranoia) Depression Agitated state Unusual dreams Nightmares Delirium	Psychotic reactions with self-harming behavior, including suicidal ideation or actions (see section "Special warnings and precautions for use") Mania
Nervous system*	Headache Dizziness	Drowsiness Tremor Dysgeusia	Seizures (see sections "Contraindications" and "Special warnings and precautions for use") Parasthesia Memory impairment	Peripheral sensory neuropathy (see section "Special warnings and precautions for use") Peripheral sensorimotor neuropathy (see section "Special warnings and precautions for use") Parosmia, including anosmia Dyskinesia (movement coordination disorder) Extrapyramidal disorders Ageusia Syncope Benign intracranial hypertension Myoclonus
Eye organs*			Visual disturbances, such as blurred vision (see section "Special warnings and precautions for use")	Transient loss of vision (see section "Special warnings and precautions for use") Uveitis
Ear and labyrinth organs*		Vertigo	Tinnitus	Hearing loss Hearing impairment
Heart**			Tachycardia Palpitations	Ventricular tachycardia, which may lead to cardiac arrest Ventricular arrhythmia and torsades de pointes (mainly in patients with risk factors for QT interval prolongation) Prolonged QT interval on ECG (see sections "Special warnings and precautions for use" and "Overdose")
Vascular system**	Phlebitis — only with intravenous administration		Hypotension
Respiratory system		Dyspnea		Bronchospasm Allergic pneumonia
Gastrointestinal tract	Diarrhea Vomiting Nausea	Abdominal pain Dyspepsia Abdominal distension Constipation		Hemorrhagic diarrhea, which in very rare cases may indicate enterocolitis, including pseudomembranous colitis (see section "Special warnings and precautions for use") Pancreatitis (see section "Special warnings and precautions for use")
Hepatobiliary system	Elevated liver enzyme levels (alanine aminotransferase [ALT] / aspartate aminotransferase [AST], alkaline phosphatase, gamma-glutamyl transferase [GGT])	Elevated blood bilirubin		Jaundice and severe liver damage, including cases of fatal acute liver failure, mainly in patients with severe underlying diseases (see section "Special warnings and precautions for use") Hepatitis
Skin and subcutaneous tissue		Rash Pruritus Urticaria Hyperhidrosis	Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special warnings and precautions for use") Drug-induced dermatitis	Toxic epidermal necrolysis Stevens-Johnson syndrome Multiform erythema Photosensitivity reactions (see section "Special warnings and precautions for use") Leukocytoclastic vasculitis Stomatitis Skin hyperpigmentation
Musculoskeletal and connective tissue*		Arthralgia Myalgia	Tendon disorders (see sections "Contraindications" and "Special warnings and precautions for use"), including tendinitis (e.g., Achilles tendon) Muscle weakness, which may be significant in patients with myasthenia gravis (see section "Special warnings and precautions for use")	Rhabdomyolysis Tendon rupture (e.g., Achilles tendon) (see sections "Contraindications" and "Special warnings and precautions for use") Ligament rupture Muscle rupture Arthritis
Renal and urinary system		Increased serum creatinine levels	Acute renal failure (e.g., due to interstitial nephritis)
General disorders and administration site conditions*	Administration site reactions (pain, redness) — only with intravenous administration	Asthenia	Pyrexia	Pain (including back, chest and limb pain)

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

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

* Very rare cases of prolonged (several months or years) disability and potentially irreversible serious adverse reactions affecting various body systems (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathies associated with paresthesia and neuralgia, fatigue, psychiatric symptoms (including sleep disorders, anxiety, panic attacks, depression, and suicidal thoughts), memory and concentration impairment, hearing, vision, taste, and smell disturbances) have been reported in association with the use of quinolones and fluoroquinolones, regardless of the presence of risk factors (see section "Special precautions for use").

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

Other adverse reactions associated with the use of fluoroquinolones: porphyria attacks in patients with porphyria.

Reporting of adverse reactions after marketing authorization is of great importance. 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 the following link: http://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions.

The medicinal product does not require special storage conditions.

Keep out of reach and sight of children.

Packaging.

5, 7, or 10 tablets in a blister; 1 blister per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

ALKALOID AD Skopje.

ALKALOID AD Skopje.

Manufacturer's address and place of business

Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.

Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.