Levoflox

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

Composition:

Active substance: levofloxacin;

1 tablet contains levofloxacin hemihydrate equivalent to levofloxacin 250 mg or 500 mg;

Excipients: microcrystalline cellulose, crospovidone, povidone, talc, magnesium stearate, hypromellose, titanium dioxide (E 171), macrogol 4000, Yellow West FCF (E 110).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

250 mg tablets: film-coated tablets, light pink in color, biconvex surface, with a score line;

500 mg tablets: film-coated tablets, oblong-shaped, light pink in color, biconvex surface, with a score line.

Pharmacotherapeutic group.

Antibacterials for systemic use. Antibacterials of the quinolone group. Fluoroquinolones. Levofloxacin. ATC code J01M A12.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial agent from 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.

Resistance.

The primary mechanism of resistance results from mutations in the gyrA gene. In vitro, cross-resistance exists 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.

The prevalence of resistance may vary geographically and over time among individual species; therefore, local information on resistance is important, especially when treating severe infections. When necessary, expert advice should be sought if local resistance prevalence renders the appropriateness of using the medicinal product questionable, at least for certain types of infections.

Breakpoints.

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

Table 1

EUCAST clinical MIC breakpoints for levofloxacin:

Pathogens	Susceptible	Resistant
Enterobacteriaceae	≤ 1 mg/l	> 2 mg/l
Pseudomonas spp.	≤ 1 mg/l	> 2 mg/l
Acinetobacter spp.	≤ 1 mg/l	> 2 mg/l
Staphylococcus spp.	≤ 1 mg/l	> 2 mg/l
S. pneumoniae 1	≤ 2 mg/l	> 2 mg/l
Streptococcus A, B, C, G	≤ 1 mg/l	> 2 mg/l
Haemophilus influenzae 2, 3	≤ 1 mg/l	> 1 mg/l
Moraxella catarrhalis 3	≤ 1 mg/l	> 1 mg/l
Intermediate values, not species-related 4	≤ 1 mg/l	> 2 mg/l

1 The breakpoint values for levofloxacin apply to high-dose therapy.

2 A low level of resistance to fluoroquinolones may be possible (MIC of ciprofloxacin 0.12−0.5 mg/L), but there is no evidence that such resistance has clinical significance in respiratory tract infections caused by Haemophilus influenzae.

3 Strains with MIC values above the breakpoint between susceptible and intermediate (moderately resistant) strains are very rare or have not yet been reported. Testing for identification and antimicrobial susceptibility on any such isolates should be repeated, and if the result is confirmed, the isolate should be sent to an authorized laboratory. Until data are available indicating clinical response for confirmed isolates with MIC above the current resistant breakpoint, they should be reported as resistant.

4 Breakpoint values for oral doses ranging from 500 mg once daily to 500 mg twice daily and intravenous doses ranging from 500 mg once daily to 500 mg twice daily.

Antibacterial spectrum.

The prevalence of resistance among selected species may vary geographically and over time. It is advisable to obtain local resistance data, especially when treating severe infections.

Typically 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: Burkholderia cepacia, Eikenella corrodens, Haemophilus influenzae, Haemophilus para-influenzae, Klebsiella oxytoca, Moraxella catarrhalis, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri.

Anaerobic bacteria: Peptostreptococcus.

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

Species for which acquired (secondary) resistance may be a problem.

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

Aerobic Gram-negative bacteria: Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter 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 may exhibit resistance to fluoroquinolones, including levofloxacin.

Pharmacokinetics.

Absorption.

There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration.

When administered orally, levofloxacin is rapidly and almost completely absorbed, with peak plasma concentrations reached within 1–2 hours after administration. 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 doses of levofloxacin 500 mg once daily is practically absent. A slight but predictable cumulative effect exists after repeated administration of 500 mg twice daily.

Penetration into tissues and body fluids.

Levofloxacin has demonstrated penetration into bronchial mucosa, bronchial secretions, lung tissue, alveolar macrophages, skin (blister 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 less than 5% of the drug excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.

Elimination.

After oral administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6−8 hours). It is primarily excreted by 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 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, as shown in 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 patients and elderly patients, except for differences related to creatinine clearance.

Gender differences.

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

Clinical characteristics.

Indications.

Levoflox, tablets, are indicated in adults for the treatment of mild to moderate infectious and inflammatory diseases caused by microorganisms sensitive to levofloxacin:

− acute bacterial sinusitis*;

− exacerbation of chronic obstructive pulmonary disease, including bronchitis*;

− community-acquired pneumonia*;

− complicated urinary tract infections (including acute pyelonephritis);

− uncomplicated cystitis*;

− chronic bacterial prostatitis;

− complicated skin and soft tissue infections*;

− pulmonary form of anthrax: post-exposure prophylaxis and definitive treatment.

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

This levofloxacin dosage form may be used to complete the course of therapy in patients who have demonstrated clinical improvement during initial treatment with levofloxacin in infusion solution form.

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

Contraindications.

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

− Epilepsy.

− Tendon-related adverse reactions following prior use of quinolones.

− Pediatric age (under 18 years).

− Pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on levofloxacin.

Iron salts, antacids containing magnesium and aluminium, didanosine. The absorption of levofloxacin is significantly reduced when administered concomitantly with antacids containing magnesium and aluminium, medicinal products containing iron salts, or didanosine (didanosine in a buffered tablet containing aluminium or magnesium). Concomitant administration of fluoroquinolones with multivitamins containing zinc results in reduced absorption. The recommended interval between administration of levofloxacin and these medicinal products should be at least 2 hours.

Calcium salts. Have minimal effect on levofloxacin absorption.

Sucralfate. The bioavailability of levofloxacin is significantly reduced when administered concomitantly with sucralfate. If a patient requires both sucralfate and levofloxacin, sucralfate should be taken at least 2 hours after levofloxacin.

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 and theophylline, NSAIDs, or other agents that lower the seizure threshold. Levofloxacin concentrations were approximately 13% higher in the presence of fenbufen compared to levofloxacin alone.

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

Tendon rupture may occur both during and up to several months after completion of therapy (see section "Special precautions").

Probenecid and cimetidine. Probenecid and cimetidine have a statistically significant effect on levofloxacin elimination. Renal clearance of levofloxacin is reduced by 24% with cimetidine and by 34% with probenecid. This is due to the ability of both medicinal products to block tubular secretion of levofloxacin. Caution should be exercised when administering levofloxacin concomitantly with medicinal products affecting tubular secretion, such as probenecid and cimetidine, particularly in patients with renal impairment.

Other information. No clinically significant effect on the pharmacokinetics of levofloxacin has been observed with concomitant administration of 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 coagulation test parameters (prothrombin time/international normalized ratio) 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 used with caution in patients receiving medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotic medicinal products).

Theophylline. Levofloxacin does not affect the pharmacokinetics of theophylline (a CYP1A2 substrate), indicating that levofloxacin is not a CYP1A2 inhibitor.

Other forms of interaction.

Food intake. No clinically significant interaction with food has been observed. Therefore, tablets may be taken independently of meals.

Alcohol consumption is not recommended during treatment with levofloxacin.

Special precautions for use.

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

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

Aneurysm and aortic dissection. Epidemiological studies indicate an increased risk of aortic aneurysm and aortic dissection following fluoroquinolone use, particularly in elderly patients.

Therefore, fluoroquinolones should be used only after careful benefit/risk assessment and consideration of alternative therapies in patients with a significant family history of aneurysmal disease, or in patients diagnosed with aortic aneurysm and/or aortic dissection, or in those with risk factors or conditions predisposing to aneurysm and aortic dissection (e.g., Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behçet’s disease, arterial hypertension, established atherosclerosis).

Patients should be advised to seek immediate medical attention in emergency departments if they experience sudden abdominal, chest, or back pain.

Tendinitis and tendon rupture.

Tendinitis may occur in isolated cases. Development of tendinitis and tendon rupture (particularly, but not limited to, Achilles tendon), sometimes bilateral, may occur as early as within the first 48 hours after initiating quinolone or fluoroquinolone therapy, and such cases have even been reported several months after discontinuation of the drug. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, patients who have undergone solid organ transplantation, patients receiving a daily dose of 1000 mg levofloxacin, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.

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 (e.g., by immobilizing the tendon). Corticosteroids are not recommended in cases of tendonopathy.

Myoclonus.

Cases of myoclonus have been reported in patients taking 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 upon the first occurrence of myoclonus, and appropriate treatment initiated.

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

Peripheral neuropathy. Cases of sensory and sensorimotor peripheral neuropathy, leading to paresthesia, hypoaesthesia, dysaesthesia, or weakness, have been reported in patients receiving quinolones and fluoroquinolones. Levofloxacin should be discontinued if a patient develops symptoms of neuropathy such as pain, burning sensations, tingling, numbness, or weakness, to prevent the development of potentially irreversible conditions.

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, it should be used with particular caution in patients predisposed to seizures and in patients with existing central nervous system (CNS) disorders, during concomitant therapy with phenylbutazone and similar NSAIDs, or with medicinal products that increase seizure susceptibility (lower the seizure threshold), such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If seizures occur, levofloxacin therapy should be discontinued.

QT interval prolongation. Cases of QT interval prolongation have been reported with fluoroquinolone use. Caution should be exercised when using fluoroquinolones, including levofloxacin, in patients with known risk factors for QT prolongation:

− congenital or acquired QT prolongation syndrome;

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

− uncorrected electrolyte imbalances (particularly hypokalemia, hypomagnesemia);

− cardiac diseases (heart failure, myocardial infarction, bradycardia).

Elderly patients and women are more sensitive to medicinal products that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used cautiously in these patient subgroups.

Hypersensitivity reactions. Levofloxacin may cause serious, potentially fatal hypersensitivity reactions (e.g., angioedema, anaphylactic shock), even after the first dose. In such cases, patients should discontinue treatment and seek immediate medical attention.

Severe bullous reactions. Severe bullous reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis (also known as Lyell’s syndrome), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) have been reported with levofloxacin use and may be life-threatening or fatal. 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 should be discontinued immediately and alternative treatment considered. Re-administration of levofloxacin is contraindicated in patients with a history of such serious reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, or DRESS syndrome) associated with prior levofloxacin use.

Superinfection. The use of levofloxacin, especially over prolonged periods, may lead to overgrowth of microorganisms not susceptible to the drug. If superinfection develops during therapy, appropriate measures should be taken.

Effect on laboratory tests.

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

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

Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of known or suspected MRSA infections, except when laboratory testing confirms susceptibility of the pathogen to levofloxacin.

Escherichia coli resistant to levofloxacin is a common cause of urinary tract infections, and this should be considered when prescribing levofloxacin for urinary tract infections. Prescribers are advised to take into account local prevalence of E. coli resistance to fluoroquinolones.

Levofloxacin may be used in the treatment of acute bacterial sinusitis and acute exacerbations of chronic bronchitis, provided these infections are properly diagnosed. Hospital-acquired infections caused by Pseudomonas aeruginosa may require combination therapy.

Clostridium difficile-associated disease. Diarrhea, particularly severe, persistent, and/or hemorrhagic, occurring during or after levofloxacin treatment, including several weeks after discontinuation, may indicate Clostridium difficile-associated disease, the most severe form of which is pseudomembranous colitis. If pseudomembranous colitis is suspected, levofloxacin should be discontinued immediately and appropriate therapy initiated promptly, including specific treatment (e.g., oral vancomycin). Antiperistaltic agents are contraindicated in this clinical situation.

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

Blood glucose alterations. As with other quinolones, alterations in blood glucose levels, including both hyperglycemia and hypoglycemia, may occur, particularly in diabetic patients receiving concomitant oral hypoglycemic agents (e.g., glyburide) or insulin. Cases of hypoglycemic coma have been reported. Blood glucose monitoring is recommended in diabetic patients.

Photosensitivity reactions. Cases of photosensitivity have been reported with levofloxacin use. To prevent photosensitivity reactions, patients taking levofloxacin should avoid strong sunlight and artificial ultraviolet radiation (e.g., UV lamps, tanning beds) during treatment and for 48 hours after discontinuation of the drug.

Patients receiving vitamin K antagonists. Due to the potential for increased coagulation test results (prothrombin time/international normalized ratio) and/or increased frequency of hemorrhagic complications 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 reported in patients taking quinolones, including levofloxacin. In very rare cases, these progressed to suicidal ideation and self-harming behavior, sometimes after only a single dose of levofloxacin. If such reactions occur, levofloxacin should be discontinued and appropriate measures taken. Levofloxacin should be used with caution in patients with psychotic disorders or a history of psychiatric illness.

Patients with glucose-6-phosphate dehydrogenase deficiency. In patients with latent or documented glucose-6-phosphate dehydrogenase deficiency, administration of quinolone antibiotics may lead to hemolytic reactions. Therefore, levofloxacin should be used with caution in these patients, with monitoring for possible hemolysis.

Patients with renal impairment. Since levofloxacin is primarily excreted by the kidneys, dose adjustment is required in patients with impaired renal function (renal insufficiency) (see section "Dosage and administration").

Hepatobiliary disorders. Cases of necrotizing hepatitis, up to life-threatening hepatic failure, have been reported with levofloxacin use, primarily in patients with severe underlying conditions such as sepsis. 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.

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

Blood disorders.

During levofloxacin therapy, 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 counts should be monitored. If abnormal results are obtained, discontinuation of levofloxacin therapy should be considered.

Important information on excipients. The medicinal product contains the colorant "Yellow West FCF" (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Due to the potential for quinolones to damage the joint cartilage in the growing organism, the drug is contraindicated in pregnant women and in women who are breastfeeding.

If pregnancy is diagnosed during treatment, the physician should be informed.

Levofloxacin does not cause impairment of fertility or reproductive function in animals.

Ability to affect reaction speed when driving or operating machinery.

Adverse neurological reactions such as dizziness, somnolence, visual and auditory disturbances may impair the ability to concentrate and react quickly. Therefore, the drug should be used with caution in patients driving vehicles or operating machinery requiring high attention.

Administration and Dosage

The medicinal product should be taken once or twice daily, regardless of food intake. Tablets should be swallowed whole with sufficient fluid.

The dosage depends on the type and severity of infection and the susceptibility of the likely pathogen. The medicinal product may 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 used.

It is recommended to continue treatment with levofloxacin for 48–72 hours after normalization of body temperature or confirmed absence of pathogens by microbiological testing.

Levofloxacin should be taken at least 2 hours before or 2 hours after taking medicinal products containing iron salts, antacids, or sucralfate, as these may reduce absorption of the drug.

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

Table 3

Indications	Daily dose	Number of doses per day	Duration of treatment
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
Uncomplicated cystitis	250 mg	Once	3 days
Complicated urinary tract infections	500 mg	Once	7–14 days
Acute pyelonephritis	500 mg	Once	7–10 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: post-exposure prophylaxis and radical treatment	500 mg	Once	8 weeks

Since levofloxacin is primarily eliminated by the kidneys, the dose should be reduced for patients with impaired renal function. Dosing for adult patients with renal impairment, in whom the creatinine clearance is less than 50 ml/min, is presented in Table 4.

Table 4

Creatinine clearance, (ml/min)	Dosing regimen (depending on infection severity 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	subsequent: 125 mg/24 hours	subsequent: 250 mg/24 hours	subsequent: 250 mg/12 hours
19−10	subsequent: 125 mg/48 hours	subsequent: 125 mg/24 hours	subsequent: 125 mg/12 hours
< 10 (also during hemodialysis and CAPD1)	subsequent: 125 mg/48 hours	subsequent: 125 mg/24 hours	subsequent: 125 mg/24 hours

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

Dosing in patients with hepatic impairment.

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

Dosing in elderly patients.

If renal function is not impaired, there is no need for dose adjustment.

Pediatric use.

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

Overdose.

According to results of toxicity studies in animals or clinical pharmacology studies conducted with supratherapeutic doses, the most significant signs expected after acute levofloxacin overdose include central nervous system (CNS) symptoms such as confusion, dizziness, altered consciousness, and seizures, as well as QT interval prolongation and gastrointestinal reactions such as mucosal erosions. In post-marketing experience, CNS effects observed in such cases have included confusion, convulsions, myoclonus, hallucinations, and tremor.

In case of overdose, careful patient monitoring, including ECG, should be performed. Treatment is symptomatic. Antacids may be used to protect the gastric mucosa. Hemodialysis, including peritoneal dialysis and continuous ambulatory peritoneal dialysis, is not effective in removing levofloxacin from the body. There are no specific antidotes.

Side effects

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Eye disorders*: rare – visual disturbances, including blurred vision; frequency not known – transient visual disturbance, temporary vision loss, uveitis.

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

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

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

Hepatobiliary disorders: common – increased liver enzyme levels (alanine aminotransferase (ALT)/aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamyl transferase (GGT)); uncommon – increased blood bilirubin; frequency not known – hepatitis, jaundice, and severe hepatic dysfunction, including cases of acute liver failure, sometimes fatal, primarily in patients with severe underlying diseases.

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

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

Metabolism and nutrition disorders: uncommon – anorexia; rare – hypoglycemia, especially in patients with diabetes mellitus, hypoglycemic coma; frequency not known – hyperglycemia; as with other fluoroquinolones, porphyria attacks may occur in patients with porphyria.

Nervous system disorders*: common – dizziness, headache; uncommon – somnolence, tremor, dysgeusia, including ageusia (loss of taste); rare – convulsions, paresthesia, memory impairment; frequency not known – sensory or sensorimotor peripheral neuropathy, parosmia, including anosmia, dyskinesia, extrapyramidal disorders, syncope, benign intracranial hypertension, myoclonus.

Psychiatric disorders*: common – insomnia; uncommon – anxiety, confusion, restlessness, nervousness; rare – depression, agitation, nightmares, abnormal dreams; frequency not known – psychotic reactions, including hallucinations, paranoia, self-destructive behavior, suicidal ideation or actions, mania.

Cardiac disorders: common – phlebitis; rare – tachycardia, palpitations, arterial hypotension; frequency not known – ventricular tachycardia, which may lead to cardiac arrest; ventricular arrhythmia; torsade de pointes arrhythmia, which may lead to cardiac arrest (mainly in patients with risk factors for QT interval prolongation); QT interval prolongation on electrocardiogram, allergic vasculitis.

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

Immune system disorders: rare – hypersensitivity reactions, angioedema; frequency not known – anaphylactic and anaphylactoid shock (anaphylactic and anaphylactoid reactions may sometimes occur after the first dose).

Skin and subcutaneous tissue disorders: uncommon – rash, pruritus, skin redness, urticaria, hyperhidrosis; rare – drug rash with eosinophilia and systemic symptoms (DRESS syndrome), localized drug eruptions; frequency not known – increased sensitivity to sunlight and ultraviolet radiation, toxic epidermal necrolysis (Lyell’s syndrome), Stevens-Johnson syndrome, exudative multiform erythema, leukocytoclastic vasculitis, stomatitis, skin hyperpigmentation. Skin and mucosal reactions may sometimes occur even after the first dose.

Musculoskeletal and connective tissue disorders*: uncommon – arthralgia, myalgia; rare – tendon disorders, including tendinitis, muscle weakness, which may be particularly significant in patients with severe myasthenia gravis; frequency not known – rhabdomyolysis, tendon rupture (may occur within 48 hours of starting treatment and may affect the Achilles tendons of both legs), ligaments, muscles, arthritis.

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

Infections and infestations: uncommon – fungal infections, including Candida species (and proliferation of other resistant microorganisms), development of secondary infections.

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

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

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life.

Film-coated tablets 250 mg – 2 years.

Film-coated tablets 500 mg – 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

5 tablets in a blister pack; 1 blister pack in a carton.

10 tablets in a blister pack; 10 blister packs in a carton.

Prescription category. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and location of its business activities.

13, Boryspylska Street, Kyiv, 02093, Ukraine.