Lyufi-500

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LUFI-500 (LUFI-500)

Composition:

Active substance: levofloxacin;

One tablet contains levofloxacin hemihydrate equivalent to 500 mg of levofloxacin;

Excipients: microcrystalline cellulose, crospovidone, hypromellose, purified talc, sodium stearyl fumarate, polyethylene glycol, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: light pink, capsule-shaped, biconvex film-coated tablets with a break line on both sides.

Pharmacotherapeutic group. Antibacterials for systemic use. Antibacterials of the quinolone group. Fluoroquinolones. Levofloxacin.

ATC code J01MA12.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone group, the S-enantiomer of the racemic mixture of the drug ofloxacin. As an antibacterial agent of the fluoroquinolone group, levofloxacin acts on the DNA gyrase/DNA topoisomerase IV complex.

Levofloxacin is characterized by a broad spectrum of antibacterial activity. Its bactericidal effect is achieved through inhibition by levofloxacin of the bacterial enzyme DNA gyrase, which belongs to type II topoisomerases. This inhibition prevents bacterial DNA from transitioning from the relaxed to the supercoiled state, thereby making further division (reproduction) of bacterial cells impossible. The spectrum of activity of levofloxacin includes Gram-positive and Gram-negative bacteria, including non-fermenting bacteria.

Typically susceptible species

Aerobic Gram-positive bacteria: Bacillus anthracis, Staphylococcus aureus methicillin-susceptible*, Staphylococcus saprophyticus, Streptococci* – groups C and G*, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes.*

Aerobic Gram-negative bacteria: Burkholderia cepacia, Eikenella corrodens, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Moraxella catarrhalis, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri.

Anaerobic bacteria: Peptostreptococcus.

Others: Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamydia trachomatis, Legionella pneumophila, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum.

Species for which acquired (secondary) resistance may be problematic

Aerobic Gram-positive bacteria: Enterococcus faecalis, Staphylococcus aureus methicillin-resistant*, coagulase-negative Staphylococcus spp.

Gram-negative aerobes: Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens.

Anaerobes: Bacteroides fragilis.

Naturally resistant strains

Aerobic Gram-positive bacteria: Enterococcus faecium.

*Methicillin-resistant S. aureus may exhibit resistance to fluoroquinolones, including levofloxacin.

Mechanism of resistance development

Resistance to levofloxacin develops through stepwise mutations in the target site of both type II topoisomerases, DNA gyrase and topoisomerase IV, in the gyrA genes. Other resistance mechanisms, such as permeability (common in Pseudomonas aeruginosa) and efflux mechanisms, may also affect susceptibility to levofloxacin.

In vitro, cross-resistance is observed between levofloxacin and other fluoroquinolones. Due to its mechanism of action, there is no cross-resistance between levofloxacin and other classes of antibacterial agents.

Breakpoints (antibiotic breakpoints or breakpoint values for the diameter of the microbial growth inhibition zone)

The clinically relevant minimum inhibitory concentration (MIC) breakpoints for levofloxacin, as recommended by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), for determining susceptibility of organisms with intermediate susceptibility and intermediate resistance are presented in Table 1.

Table 1

EUCAST clinically established MIC breakpoints for levofloxacin

Pathogens	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 urinae2	≤ 2 mg/l	> 2 mg/l
Aeromonas spp.	≤ 0.5 mg/l	> 1 mg/l
Non-species related breakpoints	≤ 0.5 mg/l	> 1 mg/l

1Only for uncomplicated urinary tract infections.

2Susceptibility may be determined based on susceptibility to ciprofloxacin.

The prevalence of resistance may vary geographically and over time for individual species; therefore, local information on resistance is very important, especially when treating severe infections. Expert advice should be sought when local resistance prevalence raises uncertainty regarding the appropriateness of using the medicinal product, at least for certain types of infections.

Pharmacokinetics.

Absorption. There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration. Orally administered levofloxacin is rapidly and almost completely absorbed, with peak plasma concentrations reached within 1–2 hours after dosing. Absolute bioavailability is 99–100%. Food has almost no effect on the absorption of levofloxacin. Steady state is achieved within 48 hours with a dosing regimen of 500 mg once or twice daily.

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

Cumulative effect after multiple dosing of levofloxacin 500 mg once daily is practically negligible. A slight but predictable cumulative effect occurs after repeated dosing of 500 mg twice daily. Steady-state distribution parameters are achieved within 3 days.

Distribution in bronchial mucosa and bronchial epithelial secretion. Peak concentrations of levofloxacin in bronchial mucosa and bronchial epithelial secretion following oral doses exceeding 500 mg were 8.3 mg/g and 10.8 mg/mL, respectively.

Distribution in lung tissue. Peak concentration of levofloxacin in lung tissue following oral doses exceeding 500 mg was approximately 11.3 mg/g, reached within 4–6 hours after administration. Concentrations in lung tissue consistently exceeded those in plasma.

Distribution in skin (blister fluid). Peak concentrations of levofloxacin in skin (blister fluid) after administration of 500 mg once or twice daily were 4 μg/mL and 6.7 μg/mL, respectively.

Distribution in cerebrospinal fluid. Levofloxacin poorly penetrates into cerebrospinal fluid.

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

Concentration in urine. Mean concentrations of levofloxacin in urine over 8–12 hours after a single oral dose of 150 mg, 300 mg, or 500 mg were 44 μg/mL, 91 μg/mL, and 200 μg/mL, respectively.

Biotransformation

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

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

Linearity

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

Patients with renal impairment

Renal impairment affects the pharmacokinetics of levofloxacin. With reduced renal function, renal excretion and clearance decrease, and elimination half-life increases (see Table 2).

Table 2

Creatinine clearance	< 20	20−49	50−80
Renal clearance (ml/min)	13	26	57
Half-life (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-related pharmacokinetic differences are clinically significant.

Clinical characteristics.

Indications.

The medicinal product Luvi-500 is indicated in adults for the treatment of the following infectious diseases:

• acute pyelonephritis and complicated urinary tract infections;
• chronic bacterial prostatitis;
• pulmonary form of anthrax: post-exposure prophylaxis and treatment.

(In the treatment of the infections listed below, the medicinal product should be used only when other antibacterial agents typically prescribed for initial treatment of these infections cannot be used):

• acute bacterial sinusitis;
• exacerbation of chronic obstructive pulmonary disease, including bronchitis;
• community-acquired pneumonia;
• complicated skin and soft tissue infections;
• uncomplicated cystitis.

Luvi-500 may be used to complete the course of therapy in patients who have shown improvement during initial treatment with an intravenous infusion solution.

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

Contraindications.

Levofloxacin is not used in:

• patients with hypersensitivity to levofloxacin or to other quinolone antimicrobial agents, or to any of the excipients of this medicinal product;
• patients with epilepsy;
• patients who have experienced tendon-related adverse reactions following previous use of quinolones;
• children and adolescents (under 18 years of age);
• during 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 concomitantly with antacids containing magnesium and aluminium, as well as with medicinal products containing iron salts or didanosine (only didanosine formulations containing aluminium or magnesium as buffering agents). Concurrent use of fluoroquinolones with multivitamins containing zinc leads to reduced oral absorption. Tablets should be taken at least 2 hours after administration of products containing divalent or trivalent cations, such as iron salts, antacids containing magnesium or aluminium, or didanosine (only didanosine formulations containing aluminium or magnesium as buffering agents). Calcium salts have minimal effect on levofloxacin absorption.

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 administration of Luvi-500 tablets.

Theophylline, fenbufen or similar non-steroidal anti-inflammatory drugs (NSAIDs)

No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant reduction in seizure threshold may occur when quinolones are used concomitantly with theophylline, NSAIDs, and other agents that lower the seizure threshold. The concentration of levofloxacin in the presence of fenbufen was approximately 13% higher than when levofloxacin was administered alone.

Systemic corticosteroids (e.g., prednisolone). Concomitant use with corticosteroids may increase the risk of tendinitis and tendon rupture.

Tendon rupture may occur both at the beginning of therapy and several months after its completion (see section "Special precautions").

Probenecid and cimetidine

Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin. Renal clearance of levofloxacin is reduced by 24% in the presence of cimetidine and by 34% in the presence of probenecid. This is explained by the fact that both drugs are capable of blocking tubular secretion of levofloxacin. However, in studies, statistically significant kinetic differences did not have clinical significance. Levofloxacin should be prescribed with caution concomitantly with medicinal products affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other drugs

It is known that the pharmacokinetics of levofloxacin is not clinically significantly affected when administered together with calcium carbonate, digoxin, glyburide, or ranitidine.

Effect of levofloxacin on other medicinal products

Cyclosporine

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

Vitamin K antagonists

When used concomitantly with vitamin K antagonists (e.g., warfarin), increased coagulation test parameters (prothrombin time/international normalized ratio) and/or bleeding, which may be severe, have been reported. Therefore, patients receiving vitamin K antagonists concurrently should have coagulation parameters monitored (see section "Special precautions").

Medicinal products that prolong the QT interval

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

Theophylline

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

Other types of interactions

Food intake

No clinically significant interaction with food has been observed. Therefore, Luvi-500 tablets may be taken independently of food intake.

Alcohol consumption is not recommended during treatment with levofloxacin.

Special precautions for use.

The drug should be avoided in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones. Treatment of these patients with levofloxacin should be initiated only if there are no alternative treatment options and after careful assessment of benefit/risk ratio.

Prolonged, disabling and potentially irreversible serious adverse reactions.

Very rarely, in patients receiving fluoroquinolones, regardless of age and existing risk factors, prolonged (lasting for months or years), disabling and potentially irreversible serious adverse reactions affecting various, and sometimes multiple simultaneously, organ systems (musculoskeletal, nervous, psychiatric, and sensory organs) have been reported. The drug should be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.

Methicillin-resistant S. aureus (MRSA).

There is a very high likelihood of cross-resistance to fluoroquinolones, including levofloxacin, in methicillin-resistant S. aureus (MRSA). 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 properly diagnosed.

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

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

Tendinitis and tendon rupture.

Tendonitis, which may lead to tendon rupture including Achilles tendon, may occur during treatment with quinolones. Tendonitis and tendon ruptures, sometimes bilateral, may occur within 48 hours of starting levofloxacin or even several months after discontinuation of levofloxacin. Patients most susceptible to tendonitis and tendon rupture include those aged 60 years and older, patients with impaired renal function, patients who have undergone solid organ transplantation, patients receiving a daily dose of 1000 mg levofloxacin, and patients receiving corticosteroids. Therefore, concomitant use of corticosteroids should be avoided.

The daily dose should be adjusted in elderly patients based on creatinine clearance. Elderly patients receiving levofloxacin should be closely monitored. At the first signs of tendinitis (e.g., painful swelling, inflammation), levofloxacin should be discontinued immediately and alternative treatment options considered. Affected limbs should be appropriately managed, for example, by immobilizing the tendon (see sections "Contraindications" and "Adverse reactions"). Corticosteroids are not recommended in cases of tendonopathy.

Clostridium difficile-associated disease.

Diarrhea, particularly severe, persistent, and/or hemorrhagic, during or after treatment with levofloxacin (including several weeks after treatment) may be a symptom of infection caused by Clostridium difficile. The severity of Clostridium difficile infection may range from moderate to life-threatening, with pseudomembranous colitis being the most severe form (see section "Adverse reactions"). It is therefore important to consider this diagnosis in patients presenting with diarrhea after administration of any antibacterial agent. If pseudomembranous colitis is suspected or confirmed, the drug should be discontinued immediately and supportive therapy initiated without delay; specific therapy (e.g., oral vancomycin) should be started if necessary. Medicinal products that inhibit intestinal motility are contraindicated in this clinical situation.

Patients predisposed to seizures.

Quinolones may lower the seizure threshold and provoke seizures. Levofloxacin is contraindicated in patients with a history of epilepsy. As with other quinolones, the medicinal product Luvi-500 should be used with extreme caution in patients predisposed to seizures, such as patients with central nervous system (CNS) disorders, concomitant therapy with fenbufen and similar NSAIDs, or medicinal products that increase seizure susceptibility (lower seizure threshold), such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If seizures occur, treatment with levofloxacin should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency.

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

Patients with renal impairment.

Since the medicinal product Luvi-500 is primarily eliminated via the kidneys, dose adjustment is required in patients with impaired renal function (renal insufficiency) (see section "Dosage and administration").

Hypersensitivity reactions.

Levofloxacin may cause serious, potentially fatal hypersensitivity reactions (e.g., angioedema, anaphylactic shock), even after the first dose (see section "Adverse reactions"). In such cases, patients should discontinue treatment immediately and seek medical advice.

Severe skin reactions.

Severe skin reactions, including toxic epidermal necrolysis (also known as Lyell's syndrome), Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported with levofloxacin use and may be life-threatening or fatal (see section "Adverse reactions"). Patients should be informed of the signs and symptoms of these severe skin reactions, and close monitoring should be established. If signs or symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative treatment considered. Re-initiation of levofloxacin treatment is contraindicated in patients who have experienced a serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome during prior levofloxacin therapy.

Alterations in blood glucose levels.

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

Prevention of photosensitization.

Although photosensitization is very rare with levofloxacin, patients should avoid exposure to strong sunlight or artificial UV radiation (e.g., UV lamps, sunbeds) during treatment and for 48 hours after discontinuation of the drug to prevent photosensitivity reactions.

Patients receiving vitamin K antagonists.

Due to the possible increase in coagulation test parameters (PT/INR) and/or increased frequency of hemorrhagic complications in patients taking Luvi-500 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 reported in patients taking quinolones, including the medicinal product Luvi-500. In very rare cases, these progressed to suicidal ideation and self-destructive behavior, sometimes after only a single dose of levofloxacin (see section "Adverse reactions"). If such reactions occur, the drug should be discontinued and appropriate measures taken. Luvi-500 should be used with caution in patients with psychotic disorders or a history of psychiatric illness.

QT interval prolongation.

Cases of QT interval prolongation have been reported with fluoroquinolone use. Fluoroquinolones, including Luvi-500, should be used with caution in patients with known risk factors for QT 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", "Dosage and administration" ("Elderly patients"), "Overdose", and "Adverse reactions").

Peripheral neuropathy.

Cases of sensory and sensorimotor peripheral neuropathy, leading to paresthesia, hyposthesia, dysesthesia, or weakness, have been reported in patients receiving quinolones and fluoroquinolones. Levofloxacin should be discontinued if patients experience symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness to prevent progression to a potentially irreversible condition.

Hepatobiliary disorders.

Cases of necrotic hepatitis up to life-threatening liver failure have been reported with levofloxacin use, primarily in patients with severe underlying conditions such as sepsis (see section "Adverse reactions"). 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, including the need for respiratory support and fatal outcomes, have been reported in patients with myasthenia gravis during post-marketing use of fluoroquinolones. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances.

If visual disturbances occur, patients should seek immediate consultation with an ophthalmologist (see sections "Ability to influence reaction speed when driving or operating machinery" and "Adverse reactions").

Superinfection.

With the use of levofloxacin, particularly prolonged use, development of opportunistic infections and overgrowth of resistant microorganisms is possible. If superinfection develops during therapy, appropriate measures should be taken.

Aortic aneurysm and dissection, cardiac valve regurgitation/insufficiency.

Epidemiological studies suggest 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 cardiac valve regurgitation/insufficiency have been reported in patients receiving fluoroquinolones (see section "Adverse reactions").

Therefore, fluoroquinolones should be used only after careful benefit/risk assessment and consideration of alternative therapeutic options in patients with a family history of aneurysm or congenital heart valve defect, or in patients with diagnosed aneurysm and/or aortic dissection, or heart valve disease, or in the presence of other risk factors or predisposing conditions:

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

The risk of aortic aneurysm and dissection and their rupture may be increased in patients receiving systemic corticosteroids concomitantly.

Patients should seek immediate medical attention in the emergency department if they experience sudden abdominal, chest, or back pain.

Patients should be advised to seek immediate medical help if they experience acute shortness of breath, new onset of 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, severe abdominal pain, or vomiting should undergo urgent medical evaluation. If acute pancreatitis is suspected, levofloxacin should be discontinued; if the diagnosis is confirmed, levofloxacin should not be restarted. Caution should be exercised in patients with a history of pancreatitis (see section "Adverse reactions").

Effect on laboratory tests.

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

Levofloxacin inhibits the growth of Mycobacterium tuberculosis, which may result in false-negative bacteriological test results in patients with tuberculosis.

Important information on excipients.

Sodium.

The medicinal product Luvi-500 contains less than 1 mmol sodium (less than 23 mg) per tablet, i.e., essentially sodium-free.

Use in children.

Safety and efficacy of levofloxacin in children and adolescents under 18 years of age have not been established. Quinolones, including levofloxacin, cause arthropathy and osteochondrosis in immature animals of various species.

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of levofloxacin in pregnant women are limited.

Due to the lack of human studies and the potential for quinolone-induced joint cartilage damage in the growing organism, the drug is contraindicated during pregnancy. If pregnancy occurs during treatment, this should be reported to the physician.

Breastfeeding period. Levofloxacin is contraindicated during breastfeeding. Information on the excretion of levofloxacin in 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 joint cartilage damage in the growing organism, the drug should not be administered to women who are breastfeeding.

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

Ability to influence reaction speed when driving or operating machinery.

Patients who drive vehicles or operate machinery should be aware of possible nervous system adverse reactions (dizziness/vertigo, paresthesia, somnolence, confusion, visual and hearing disturbances, motor disturbances).

Dosage and Administration.

Lufi-500 tablets are taken once or twice daily. The dose depends on the type and severity of infection and the susceptibility of the likely pathogen. The medicinal product can 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 forms, the same dosage may be applied.

Lufi-500 tablets should be swallowed whole with an adequate amount of liquid. For convenience in dosing, the tablet may be divided along the break line.

The tablets may be taken regardless of food intake.

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

Table 3

Recommended dosage for adult patients with normal renal function, in whom creatinine clearance is over 50 mL/min

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

Special populations

Table 4

Dosage for adult patients with renal impairment and creatinine clearance less than or equal to 50 ml/min

Creatinine clearance	Dosing regimen (depending on severity of infection and nosological form)
	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 (as well as during hemodialysis and CRRT1)	subsequent – 125 mg/ 48 hours	subsequent – 125 mg/ 24 hours	subsequent – 125 mg/ 24 hours

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

Patients with 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 normal, dose adjustment is not required (see section "Special precautions": tendinitis and tendon rupture, QT interval prolongation).

Children.

The medicinal product Lufi-500 is contraindicated in children and adolescents (see section "Contraindications").

Overdose.

Symptoms. Based on animal toxicity studies or clinical pharmacology studies performed using supratherapeutic doses, the most significant signs expected after acute levofloxacin overdose include central nervous system (CNS) effects such as confusion, dizziness, altered consciousness, and seizures, as well as QT interval prolongation and gastrointestinal reactions such as nausea and mucosal erosions. In post-marketing experience, CNS effects observed in such cases have included confusion, seizures, hallucinations, and tremor.

Treatment is symptomatic. ECG monitoring should be considered due to the potential for QT interval prolongation. Antacids should be administered to protect the gastric mucosa.

Hemodialysis, including peritoneal dialysis or CAPD, is not effective in removing levofloxacin from the body. There are no specific antidotes.

Adverse reactions.

The adverse reactions listed below are categorized by organ systems and frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from the available data).

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

System Organ Class	Common	Uncommon	Rare	Frequency not known
Infections and infestations		fungal infections, including infections caused by Candida species; pathogenic microorganism resistance
Blood and lymphatic system disorders		leukopenia, eosinophilia	thrombocytopenia, neutropenia	pancytopenia, agranulocytosis, hemolytic anemia
Immune system disorders			angioedema, hypersensitivity (see section "Special precautions")	anaphylactic shock, anaphylactoid shock (see section "Special precautions")
Endocrine disorders			syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition disorders		anorexia	hypoglycemia, especially in patients with diabetes mellitus; hypoglycemic coma (see section "Special precautions")	hyperglycemia (see section "Special precautions")
Psychiatric disorders*	insomnia	anxiety, confusion, restlessness	psychotic reactions (e.g., with hallucinations, paranoia); depression, agitation, delirium, unusual dreams, nightmares	psychotic reactions with self-destructive behavior, including suicidal ideation or actions (see section "Special precautions")
Nervous system disorders*	headache, dizziness	drowsiness, tremor, dysgeusia (subjective taste disturbance)	seizures (see sections "Contraindications" and "Special precautions"); paraesthesia, memory impairment	peripheral sensory or sensorimotor neuropathy (see section "Special precautions"); olfactory disturbances (parosmia), including anosmia (loss of smell); dyskinesia (movement coordination disorder); extrapyramidal disorders, ageusia, syncope (fainting); benign intracranial hypertension
Eye disorders*			visual disturbances such as blurred vision (see section "Special precautions")	transient loss of vision (see section "Special precautions"); uveitis, optic neuritis
Ear and labyrinth disorders*		vertigo	tinnitus	hearing loss, hearing impairment
Cardiac disorders**			tachycardia, palpitations	ventricular tachycardia, which may lead to cardiac arrest; torsades de pointes ventricular arrhythmia (mainly in patients with risk factors for QT interval prolongation); QT interval prolongation on ECG (see sections "Special precautions" and "Overdose")
Vascular disorders**	apply only to the intravenous formulation: phlebitis		hypotension
Respiratory, thoracic and mediastinal disorders		dyspnea		bronchospasm, allergic pneumonia
Gastrointestinal disorders	diarrhea, vomiting, nausea	abdominal pain, dyspepsia, bloating, constipation		hemorrhagic diarrhea, which in very rare cases may indicate enterocolitis, including pseudomembranous colitis (see section "Special precautions"); pancreatitis
Hepatobiliary disorders	elevated liver enzyme levels (ALT/AST, alkaline phosphatase, GGT)	increased blood bilirubin levels		jaundice and severe liver injury, including cases of fatal acute liver failure, primarily in patients with serious underlying diseases (see section "Special precautions"); hepatitis
Skin and subcutaneous tissue disorders		rash, pruritus, urticaria, hyperhidrosis	drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special precautions"); persistent drug eruptions	toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, photosensitization reactions (see section "Special precautions"); leukocytoclastic vasculitis, stomatitis
Musculoskeletal and connective tissue disorders*		arthralgia, myalgia	tendon disorders (see sections "Contraindications" and "Special precautions"), including tendinitis (e.g., Achilles tendon); muscle weakness, which may be of particular importance in patients with myasthenia gravis (see section "Special precautions")	rhabdomyolysis, tendon rupture (e.g., Achilles tendon) (see sections "Contraindications" and "Special precautions"); ligament rupture, muscle rupture, arthritis
Renal and urinary disorders		increased serum creatinine levels	acute renal failure (e.g., due to interstitial nephritis)
General disorders and administration site conditions*	apply only to the intravenous formulation: infusion site reaction (pain, redness)	asthenia	fever	pain (including back, chest and limb pain)

aAnaphylactic and anaphylactoid reactions may sometimes occur even after administration of the first dose of the drug.

bSkin and mucous membrane reactions are sometimes possible even after administration of the first dose of the drug.

*In very rare cases, in patients receiving quinolones and fluoroquinolones, regardless of the presence of risk factors, there have been reports of long-term (lasting for months or years), disabling and potentially irreversible serious adverse reactions affecting various, and sometimes several simultaneously, body systems and sensory organs (including reactions such as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbances, neuropathy associated with paresthesia, depression, fatigue, memory impairment, sleep disturbances, hearing, vision, taste and smell disturbances) (see section "Special precautions for use").

Other adverse reactions associated with fluoroquinolone use:

• Porphyria attacks in patients with known porphyria.

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

Reporting of suspected adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25°C, in a dry, light-protected place, out of reach of children.

Packaging. 5 tablets in a blister; 1 blister in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Ipca Laboratories Limited.

Manufacturer's address and location of its business activity.

Plot No. 255/1, Village – Atul, U.T. Dadra and Nagar Haveli, 396230 Silvassa, India.