Levasect

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

Composition:

Active substance: levofloxacin;

One film-coated tablet contains levofloxacin hemihydrate equivalent to 500 mg of levofloxacin;

Excipients: microcrystalline cellulose, crospovidone, povidone, colloidal anhydrous silicon dioxide, talc, magnesium stearate; coating – Opadry 03B565038 (sorbic acid, hydroxypropylcellulose, titanium dioxide (E 171), hypromellose, vanillin, quinoline yellow aluminum lake (E 104), polysorbates, propylene glycol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: brown-colored, elongated, biconvex film-coated tablets with an imprint "B500" on one side and smooth on the other side.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Antibacterial agents of the quinolone group. Fluoroquinolones. Levofloxacin.

ATC code J01MA12.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial medicinal product of the fluoroquinolone class and is the S-enantiomer of the racemic active substance ofloxacin.

Mechanism of action

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

Pharmacokinetic/pharmacodynamic (PK/PD) relationship

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

Mechanism(s) of resistance development

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

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.

Breakpoint concentrations

EUCAST (European Committee on Antimicrobial Susceptibility Testing) recommends MIC breakpoints for levofloxacin to determine susceptibility of organisms classified as intermediate susceptible and intermediate resistant, as shown in Table 1 based on MIC testing data (mg/L).

Table 1

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

Organism	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 (groups 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
PK-PD breakpoints (non-species related)	≤ 0.5 mg/L	> 1 mg/L
1Only uncomplicated urinary tract infections. 2Susceptibility may depend on susceptibility to ciprofloxacin.

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

Generally susceptible species

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

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

Anaerobes: Peptostreptococcus.

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

Species with possible acquired resistance

Gram-positive aerobes: Enterococcus faecalis, methicillin-resistant# Staphylococcus aureus, 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

Gram-positive aerobes: Enterococcus faecium.

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

Pharmacokinetics

Absorption. After oral administration, levofloxacin is rapidly and almost completely absorbed; maximum plasma concentration (Cmax) is reached within 1–2 hours after dosing. Absolute bioavailability is 99–100%. Food intake has a negligible effect on its absorption. Steady-state levels are achieved within 48 hours after administration 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 good tissue penetration.

Penetration into tissues and body fluids. Levofloxacin has been shown to penetrate bronchial mucosa, epithelial lining fluid, alveolar macrophages, lung tissue, skin (bulla fluid), prostate tissue, and urine. However, levofloxacin penetrates poorly into cerebrospinal fluid.

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

Elimination. After both oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6–8 hours). Elimination occurs primarily via the kidneys (over 85% of the administered dose). The mean apparent total body clearance of levofloxacin after a single 500 mg oral dose was 175 ± 29.2 mL/min.

There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration, suggesting that oral and intravenous routes of administration are interchangeable.

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

Special populations

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

Pharmacokinetics in renal impairment after a single 500 mg oral dose

Creatinine clearance (ml/min)	< 20	20–49	50–80
Renal clearance (ml/min)	13	26	57
Elimination half-life (hours)	35	27	9

Elderly patients

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

Gender differences

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

Clinical characteristics.

Indications.

The medicinal product Levasept is indicated for the treatment of the following infections in adults:

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

When treating the infections listed below, the medicinal product Levasept should be used only if other antibacterial agents typically prescribed for 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.

The Levasept tablet formulation may also be used to complete a course of therapy in patients who have shown clinical improvement during initial treatment with intravenous levofloxacin.

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

Contraindications.

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

Epilepsy.

History of tendon rupture associated with the use of fluoroquinolones.

Paediatric age.

Pregnancy or 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 co-administered with iron salts, antacids containing magnesium or aluminium, or didanosine (this applies only to didanosine formulations with buffering agents containing aluminium or magnesium). Concurrent administration of fluoroquinolones with multivitamins containing zinc results in reduced oral absorption.

Medicinal products containing divalent or trivalent cations, such as iron salts, zinc salts, antacids containing magnesium or aluminium, or didanosine (this applies only to didanosine formulations with buffering agents containing aluminium or magnesium), should not be taken within 2 hours before or after oral administration of levofloxacin tablets (see section "Dosage and administration"). Calcium salts have minimal effect on the absorption of levofloxacin when administered orally.

Sucralfate

Bioavailability of levofloxacin is significantly reduced when administered concomitantly with sucralfate. If a patient requires both sucralfate and levofloxacin, it is preferable to administer sucralfate 2 hours after taking Levasept tablets (see section "Dosage and administration").

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

No pharmacokinetic interaction between levofloxacin and theophylline was observed in clinical studies. However, a significant reduction in the cerebral seizure threshold may occur when quinolones are used concomitantly with theophylline, NSAIDs, or other drugs that lower the seizure threshold.

Levofloxacin concentrations were approximately 13% higher in the presence of fenbufen compared to administration of levofloxacin alone.

Probenecid and cimetidine

Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin.

Renal clearance of levofloxacin is reduced by 24% when co-administered with cimetidine and by 34% with probenecid. This is explained by the fact that both drugs can inhibit tubular secretion of levofloxacin. However, in studies, these statistically significant kinetic differences did not have clinical significance.

Levofloxacin should be administered with caution together with medicinal products affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other information

Clinical pharmacological studies have demonstrated that no clinically significant effect on the pharmacokinetics of levofloxacin occurred when levofloxacin was administered concomitantly with calcium carbonate, digoxin, glyburide, or ranitidine.

Effect of levofloxacin on other medicinal products

Cyclosporine

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

Vitamin K antagonists

When administered concomitantly with vitamin K antagonists (e.g., warfarin), increased coagulation test parameters (prothrombin time/international normalized ratio (PT/INR)) and/or bleeding events, 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, and antipsychotics); see section "Special precautions".

Other significant information

A pharmacokinetic interaction study did not demonstrate any effect of levofloxacin on the pharmacokinetics of theophylline (a marker substrate for the CYP1A2 enzyme), indicating that levofloxacin is not an inhibitor of CYP1A2.

Other forms of interaction

Food intake

No clinically significant interaction with food has been observed. Therefore, Levasept tablets can be taken independently of food intake.

Special precautions for use.

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

MRSA (Methicillin-resistant S. aureus)

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 when laboratory testing has confirmed susceptibility of the pathogen to levofloxacin (use of standard antibacterial agents for MRSA infections is considered inappropriate).

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

Resistance to fluoroquinolones in E. coli (the most common pathogen causing urinary tract infections) varies across EU countries. Physicians should take into account local prevalence of fluoroquinolone resistance in E. coli when prescribing fluoroquinolones.

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

Long-term, disabling and potentially irreversible serious adverse reactions

Very rarely, patients receiving quinolones and fluoroquinolones, regardless of age or risk factors, have reported long-term (lasting months or years), disabling and potentially irreversible adverse reactions affecting various, and sometimes multiple, organ systems (including musculoskeletal, nervous, psychiatric, and sensory systems). The drug should be discontinued immediately at the first signs or symptoms of any adverse reaction, and medical advice should be sought.

Tendinitis and tendon rupture

Tendinitis and tendon ruptures (including, but not limited to Achilles tendon), sometimes bilateral, may occur within 48 hours of starting quinolone or fluoroquinolone therapy and even several months after discontinuation of treatment.

Patients most susceptible to tendinitis and tendon rupture include elderly patients, those with impaired renal function, solid organ transplant recipients, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant use of corticosteroids should be avoided.

Levofloxacin should be discontinued immediately at the first signs of tendinitis (e.g., painful swelling, inflammation), and alternative therapy should be considered. Appropriate management (e.g., immobilization) of the affected limb(s) should be initiated. Corticosteroids should not be used in cases of tendonopathy.

Clostridium difficile-associated disease (CDAD)

Diarrhea, particularly severe, persistent, and/or hemorrhagic, during or after treatment (up to several weeks after completion of therapy) may be a symptom of Clostridium difficile-associated disease (CDAD). The severity of CDAD may range from mild to life-threatening, with the most severe form being pseudomembranous colitis. Therefore, it is important to consider the possibility of this condition in patients with severe diarrhea during or after levofloxacin therapy. If pseudomembranous colitis is suspected or confirmed, levofloxacin should be discontinued immediately and appropriate therapy initiated promptly (e.g., oral metronidazole or vancomycin).

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 (see section "Contraindications"). As with other quinolones, Levasept should be used with particular caution in patients predisposed to seizures or those receiving concomitant therapy with agents that lower the seizure threshold, such as theophylline. If seizures occur, levofloxacin therapy should be discontinued.

Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency

Patients with latent or manifest deficiency in glucose-6-phosphate dehydrogenase activity may be prone to hemolytic reactions during treatment with quinolone-class antibacterial agents. Therefore, patients receiving levofloxacin should be monitored for possible development of hemolysis.

Patients with renal impairment

Since levofloxacin is primarily excreted by the kidneys, dose adjustment is required in patients with impaired renal function.

Hypersensitivity reactions

Levofloxacin may cause serious, potentially fatal hypersensitivity reactions (e.g., angioedema up to anaphylactic shock) after administration of the initial dose. Patients should discontinue treatment immediately and seek medical advice or emergency care, where appropriate emergency measures should be initiated.

Severe skin adverse reactions

Severe cutaneous adverse reactions (SCAR), including toxic epidermal necrolysis (also known as Lyell’s syndrome), Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with levofloxacin use, which may be life-threatening or fatal. Patients should be informed about the signs and symptoms of severe skin reactions and closely monitored during treatment. If such signs or symptoms appear, levofloxacin should be discontinued immediately and alternative therapy considered. Re-initiation of levofloxacin treatment in patients who have experienced serious reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, or DRESS is absolutely contraindicated.

Glucose level alterations

Alterations in blood glucose levels (both hyperglycemia and hypoglycemia) have been reported with all quinolones, particularly in diabetic patients receiving concomitant oral hypoglycemic agents (including glibenclamide) or insulin. Cases of hypoglycemic coma have been documented. Blood glucose levels should be monitored in diabetic patients.

Levofloxacin should be discontinued immediately if the patient reports changes in blood glucose levels, and alternative antibacterial therapy not involving fluoroquinolones should be prescribed.

Phototoxicity prevention

Cases of phototoxicity have been reported with levofloxacin use. To avoid this, patients should avoid exposure to strong sunlight or artificial UV radiation (e.g., UV lamps, tanning beds) during levofloxacin treatment and for 48 hours after discontinuation of the drug.

Patients receiving vitamin K antagonists

Due to the potential risk of increased coagulation test parameters (prothrombin time/INR) and/or bleeding in patients taking levofloxacin concomitantly with vitamin K antagonists (e.g., warfarin), coagulation parameters should be monitored if these drugs are used together.

Psychotic reactions

Psychotic reactions have been reported in patients taking quinolones, including levofloxacin.

In very rare cases, these reactions progressed to suicidal ideation and self-destructive behavior, sometimes after a single dose of levofloxacin. If such reactions occur, levofloxacin should be discontinued immediately at the first signs or symptoms, and the patient should seek medical advice.

Alternative therapy not involving fluoroquinolones is recommended, along with appropriate interventions.

Levofloxacin should be used with caution in patients with a history of psychotic disorders or psychiatric illness.

QT interval prolongation

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

• congenital long QT syndrome;
• concomitant use of medicinal products known to prolong the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics);
• uncorrected electrolyte imbalances (e.g., hypokalemia, hypomagnesemia);
• cardiac disease (e.g., heart failure, myocardial infarction, bradycardia).

Elderly patients and 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.

Peripheral neuropathy

Cases of sensory or sensorimotor peripheral neuropathy have been reported in patients receiving quinolones and fluoroquinolones, leading to paresthesia, hypoesthesia, dysesthesia, or weakness. If symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness occur, patients should inform their physician before continuing treatment to prevent the development of potentially irreversible conditions.

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 seek medical advice 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 fatal outcomes and the need for respiratory support, have been reported in post-marketing experience in patients with myasthenia gravis receiving fluoroquinolones. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances

If visual disturbances or other ocular effects occur, immediate consultation with an ophthalmologist is required (see sections "Ability to affect reaction speed when driving or operating machinery" and "Adverse reactions").

Superinfection

With levofloxacin use, particularly prolonged use, overgrowth of resistant microorganisms may occur. 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. Positive opiate test results may require confirmation using more specific methods.

Levofloxacin inhibits the growth of Mycobacterium tuberculosis, which may lead to false-negative results in bacteriological testing of patients with tuberculosis.

Aortic aneurysm or dissection and cardiac valve regurgitation/insufficiency

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

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

• for both aortic aneurysm/dissection and cardiac valve regurgitation/insufficiency (e.g., connective tissue disorders such as Marfan syndrome, Ehlers-Danlos syndrome, or 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, or known atherosclerosis, or Sjögren’s syndrome), or additionally
• for cardiac valve regurgitation/insufficiency (e.g., infective endocarditis).

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

Patients should seek immediate medical attention in case of sudden abdominal, chest, or back pain.

Patients should be advised to seek immediate medical help in case of acute dyspnea, 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 characteristic symptoms of acute pancreatitis. Patients experiencing nausea, malaise, abdominal discomfort, acute abdominal pain, or vomiting should be evaluated immediately. Levofloxacin should be discontinued if acute pancreatitis is suspected and not restarted if diagnosis is confirmed. Caution should be exercised when treating patients with a history of pancreatitis.

Excipients

This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., it is considered essentially sodium-free.

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 in terms of reproductive toxicity. However, due to the lack of human studies and experimental data suggesting potential fluoroquinolone-induced damage to cartilage in the growing organism, Levasept should not be prescribed to pregnant women (see section "Contraindications").

Breastfeeding

Levasept is contraindicated during breastfeeding.

There is insufficient information on the excretion of levofloxacin into human breast milk, although other fluoroquinolones are excreted into breast milk. Due to the lack of human studies and experimental data indicating potential fluoroquinolone-induced damage to cartilage in the growing organism, Levasept should not be administered to breastfeeding women (see section "Contraindications").

Fertility

Levofloxacin did not cause disturbances in fertility or reproductive function in rats.

Ability to affect reaction speed when driving or operating machinery.

Levasept has a minor or moderate influence on the ability to drive or operate machinery. Some adverse effects (e.g., dizziness/vertigo, somnolence, visual disturbances) may impair a patient’s ability to concentrate and react, thus potentially posing a danger in situations where such ability is particularly important (e.g., driving or operating machinery).

Method of administration and dosage.

Levascept tablets should be taken 1–2 times daily. The dosage depends on the type and severity of infection, as well as on the susceptibility of the probable causative pathogen.

Levascept tablets can also be used to complete the full course of therapy in patients who have shown improvement during initial treatment with intravenous levofloxacin. Since the parenteral and oral formulations are bioequivalent, the same dosage may be used.

Dosage

Recommended dosages of levofloxacin in tablet form are provided in Tables 3–4 below.

Table 3

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

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

Special populations

Table 4

Dosage 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
	first dose – 250* mg	first dose – 500 mg	first 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 (also during hemodialysis and CAPD1)	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.

* Since the tablet is not divisible, in case a dose lower than 500 mg is prescribed, levofloxacin preparations with appropriate dosage strengths should be used.

Dosing in patients with hepatic impairment. Dose adjustment is not necessary, as levofloxacin is minimally metabolized in the liver and primarily excreted by the kidneys.

Dosing in elderly patients. If renal function is not impaired, dose adjustment is not required.

Method of administration

Levasept tablets should be swallowed whole, without chewing, with sufficient amount of liquid. Tablets may be taken regardless of food intake.

The medicinal product should be administered at least 2 hours before or 2 hours after administration of iron salts, zinc salts, antacids containing magnesium or aluminum, didanosine (only formulations containing aluminum or magnesium in buffering agents), and sucralfate, as these agents may reduce absorption.

Children.

Levasept is contraindicated in children under 18 years of age.

Overdose.

According to animal toxicity studies or clinical pharmacological studies using supratherapeutic doses, the most important signs expected after acute levofloxacin overdose include central nervous system effects (confusion, dizziness, altered consciousness, seizures); gastrointestinal reactions such as nausea and mucosal erosions; and QT interval prolongation. During post-marketing use, CNS effects including confusion, seizures, hallucinations, and tremor have been reported.

Treatment: symptomatic. ECG monitoring should be performed due to the possibility of QT interval prolongation. Antacid agents should be used to protect 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 information below is based on data from clinical trials involving more than 8,300 patients and extensive post-marketing experience.

The frequency of adverse reactions was defined using the following criteria: very common (> 1/10), common (from ≥ 1/100 to < 1/10), uncommon (from > 1/1,000 to < 1/100), rare (from > 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

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

Infections and infestations:

Uncommon: fungal infections, including Candida species, microbial resistance.

Blood and lymphatic system disorders:

Uncommon: leucopenia, eosinophilia;
Rare: thrombocytopenia, neutropenia;
Frequency not known: agranulocytosis, pancytopenia, haemolytic anaemia.

Immune system disorders:

Rare: angioedema, hypersensitivity (see section "Special warnings and precautions for use");
Frequency not known: anaphylactic shock, anaphylactoid shock (see section "Special warnings and precautions for use").

Metabolism and nutrition disorders:

Uncommon: anorexia;
Rare: hypoglycaemia, particularly in patients with diabetes, hypoglycaemic coma (see section "Special warnings and precautions for use");
Frequency not known: hyperglycaemia (see section "Special warnings and precautions for use").

Endocrine system disorders:

Rare: syndrome of inappropriate secretion of antidiuretic hormone (SIADH).

Psychiatric disorders*:

Common: insomnia;
Uncommon: nervousness, confusion, anxiety;
Rare: psychotic disorders (including hallucinations, paranoia), depression, agitation, unusual dreams, night terrors;
Frequency not known: psychotic reactions with self-destructive behaviour, including suicidal ideation or actions (see section "Special warnings and precautions for use").

Nervous system disorders*:

Common: headache, dizziness;
Uncommon: somnolence, tremor, dysgeusia;
Rare: convulsions (see sections "Contraindications" and "Special warnings and precautions for use"), paraesthesia;
Frequency not known: sensory or sensorimotor peripheral neuropathy (see section "Special warnings and precautions for use"), parosmia including anosmia, dyskinesia, extrapyramidal disorders, ageusia, syncope, benign intracranial hypertension.

Eye disorders*:

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

Ear and labyrinth disorders*:

Uncommon: vertigo;
Rare: tinnitus;
Frequency not known: hearing impairment, hearing loss.

Cardiac disorders**:

Rare: tachycardia, palpitations;
Frequency not known: ventricular tachycardia that may lead to cardiac arrest, ventricular arrhythmia and torsade de pointes arrhythmia, reported primarily in patients with risk factors for QT interval prolongation, QT prolongation on ECG (see sections "Special warnings and precautions for use" and "Overdose").

Vascular disorders:

Rare: arterial hypotension.

Respiratory, thoracic and mediastinal disorders:

Uncommon: dyspnoea;
Frequency not known: bronchospasm, allergic pneumonitis.

Gastrointestinal disorders:

Common: diarrhoea, nausea, vomiting;
Uncommon: abdominal pain, dyspepsia, bloating, constipation;
Frequency not known: haemorrhagic diarrhoea, which in very rare cases may indicate enterocolitis, including pseudomembranous colitis (see section "Special warnings and precautions for use"), pancreatitis.

Hepatobiliary disorders:

Common: increased liver enzyme levels (ALT/AST, alkaline phosphatase, GGT);
Uncommon: increased blood bilirubin;
Frequency not known: jaundice and severe hepatic injury, including cases of acute liver failure (sometimes fatal), predominantly in patients with severe underlying diseases (see section "Special warnings and precautions for use"), hepatitis.

Skin and subcutaneous tissue disorders:

Uncommon: rash, pruritus, urticaria, hyperhidrosis;
Rare: drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Special warnings and precautions for use"), persistent drug eruption;
Frequency not known: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, photosensitivity reactions (see section "Special warnings and precautions for use"), leukocytoclastic vasculitis, stomatitis.

Musculoskeletal and connective tissue disorders:

Uncommon: arthralgia, myalgia;
Rare: tendon disorders (see sections "Contraindications" and "Special warnings and precautions for use"), including tendinitis, e.g. Achilles tendon, muscle weakness which may be particularly significant in patients with myasthenia gravis (see section "Special warnings and precautions for use");
Frequency not known: rhabdomyolysis, tendon rupture (e.g. Achilles tendon) (see sections "Contraindications" and "Special warnings and precautions for use"), ligament ruptures, muscle ruptures, arthritis.

Renal and urinary disorders:

Uncommon: increased blood creatinine levels;
Rare: acute renal failure (e.g. due to interstitial nephritis).

General disorders*:

Uncommon: asthenia;
Rare: pyrexia;
Frequency not known: pain (including back, chest and limb pain).

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

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

*Very rare cases of long-lasting (up to months or years), disabling and potentially irreversible serious adverse reactions affecting multiple organs and body functions have been reported with quinolones and fluoroquinolones (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathies associated with paraesthesia, depression, fatigue, memory impairment, sleep disturbances, hearing, vision, taste and smell disturbances), regardless of pre-existing risk factors (see section "Special warnings and precautions for use").

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

Other adverse reactions associated with fluoroquinolone use include:

• Acute attacks of porphyria in patients with porphyria.

Reporting suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 30°C, in a place inaccessible to children.

Packaging. 5 tablets in a blister, 1 blister in a cardboard pack (pack size №5); 10 tablets in a blister, 1 blister in a cardboard pack (pack size №10).

Prescription status. Prescription only.

Manufacturer. Bafna Pharmaceuticals Ltd., India / Bafna Pharmaceuticals Ltd., India.

Manufacturer's address and location of operations.
147, Madhavaram Red Hills Road, Grantlyon Village, Vadakarai, Chennai, Tamil Nadu IN 600052, India / 147, Madhavaram Red Hills Road Grantlyon Village Vadakarai Chennai Tamil Nadu IN 600052, India.

Marketing Authorization Holder. JIVDHARA PHARMA PRIVATE LIMITED.

Address of Marketing Authorization Holder. 504, Block-B, Shiv Angan Complex, Sallaiya, Bhopal, Madhya Pradesh, 462026, India / 504, Block-B, Shiv Angan Complex, Sallaiya, Bhopal, Madhya Pradesh, 462026, India.