Levaxela

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Levaxela® (Levaxela®)

Composition:

Active substance: levofloxacin;

1 tablet contains levofloxacin 250 mg or 500 mg as levofloxacin hemihydrate;

Excipients: microcrystalline cellulose, hydroxypropylcellulose, crospovidone (type A), magnesium stearate;

Coating: hypromellose, titanium dioxide, macrogol 4000, yellow FCF (E 110), indigo carmine, iron oxide red, iron oxide yellow – only for 500 mg.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

250 mg tablets: pink, elongated, biconvex tablets with a score line;

500 mg tablets: orange, elongated, biconvex tablets with a score line.

Pharmacotherapeutic group.

Antibacterials for systemic use. Fluoroquinolones. Levofloxacin.

ATC code J01MA12.

Pharmacological properties.

Pharmacodynamics.

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

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

Pharmacokinetic/pharmacodynamic relationship. The extent of antibacterial activity of levofloxacin depends on the ratio of maximum serum concentration (Cmax) or area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC).

Mechanism of resistance. The primary mechanism of resistance results from mutations in the gyr-A genes. 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.

Breakpoints.

The recommended breakpoints for levofloxacin minimum inhibitory concentration (MIC) values established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), which distinguish susceptible microorganisms from intermediate (moderately resistant) organisms, and intermediate from resistant organisms, are presented in Table 1 of MIC testing (mg/L).

Table 1

Clinical breakpoints for levofloxacin (version 10.0, 2020-01-01):

Pathogen	Susceptible	Resistant
Enterobacteriaceae	≤ 0.5 mg/L	> 1 mg/L
Pseudomonas spp.	≤ 0.001 mg/L	> 1 mg/L
Acinetobacter spp.	≤ 0.5 mg/L	> 1 mg/L
Staphylococcus spp. Coagulase-negative staphylococci	≤ 0.001 mg/L	> 1 mg/L
Enterococcus spp.1	≤ 4 mg/L	> 4 mg/L
S. pneumoniae	≤ 0.001 mg/L	> 2 mg/L
Streptococcus A, B, C, G	≤ 0.001 mg/L	> 2 mg/L
H. influenzae	≤ 0.06 mg/L	> 0.06 mg/L
M. 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.	≤ 0.05 mg/L	> 1 mg/L
PK-PD (non-species-related) breakpoints	≤ 0.5 mg/L	> 1 mg/L

1. Only uncomplicated urinary tract infections

2. Susceptibility depends on sensitivity to ciprofloxacin.

The prevalence of resistance may vary geographically and over time for selected species; it is desirable to obtain local information on resistance, especially when treating severe infections. Advice from a specialist should be sought when local resistance prevalence is such that the benefit of the agent is at least doubtful in some types of infections.

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

* Mechanism of resistance of Staphylococcus aureus probably involves cross-resistance to fluoroquinolones, including levofloxacin.

Pharmacokinetics.

Absorption

Levofloxacin is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations (C_max) reached within 1–2 hours. Absolute bioavailability is approximately 99–100%.

Food has almost no effect on the absorption of levofloxacin.

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

Distribution

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

Penetration into tissues and body fluids

Levofloxacin penetrates well into bronchial mucosa, epithelial lining fluid, alveolar macrophages, lung tissue, skin (blister fluid), prostate tissue, and urine. However, levofloxacin penetrates poorly into cerebrospinal fluid.

Biotransformation

Levofloxacin undergoes minimal metabolism. The metabolites are 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 and intravenous infusion, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6–8 hours). Elimination occurs primarily via the kidneys (more than 85% of the administered dose). The mean total systemic clearance of levofloxacin after a single 500 mg dose was 175 ± 29.2 mL/min. There is no significant difference in the pharmacokinetics of levofloxacin after oral administration versus intravenous infusion, indicating interchangeability of these routes (oral and intravenous).

Linearity

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

Special patient groups

Patients with renal impairment

Renal function impairment affects the pharmacokinetics of levofloxacin. In renal impairment, renal elimination is reduced, clearance is decreased, and elimination half-life is prolonged (see 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
Half-life (hours)	35	27	9

Elderly patients

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

Gender differences

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

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to the drug:

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

Levaxela® should be used to treat the following infections only when it is considered inappropriate to use antibacterial agents usually recommended for treatment of such infections:

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

Levaxela® may also be used to complete therapy in patients who have shown improvement during initial intravenous administration of levofloxacin.

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

Contraindications.

• Hypersensitivity to levofloxacin, to other quinolones, or to any component of the drug;
• Epilepsy;
• Tendon damage associated with prior use of fluoroquinolones;
• Pediatric age (under 18 years);
• Pregnancy and breastfeeding.

Interaction with other medicinal products and other types of interactions.

Effect of other medicinal products on levofloxacin

Iron salts, zinc salts, antacids containing magnesium or aluminium, didanosine

Absorption of levofloxacin is significantly reduced when iron salts, magnesium- or aluminium-containing antacids, or didanosine (this applies only to medicinal forms of didanosine containing aluminium- or magnesium-based buffering agents) are administered simultaneously with the drug. Concurrent administration of fluoroquinolones and multivitamin preparations containing zinc reduces their oral absorption. It is not recommended to use products containing divalent or trivalent cations, such as iron salts, zinc salts, magnesium- or aluminium-containing antacids, or didanosine (this applies only to medicinal forms of didanosine containing aluminium- or magnesium-based buffering agents), within 2 hours before or after taking the drug (see section "Dosage and administration"). Calcium salts have minimal effect on the oral absorption of levofloxacin.

Sucralfate

The bioavailability of levofloxacin tablets 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 the drug (see section "Dosage and administration").

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

No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant lowering of the seizure threshold may occur when quinolones are used concomitantly with theophylline, NSAIDs, and other medicinal products that reduce the seizure threshold. The concentration of levofloxacin in the presence of fenbufen was approximately 13% higher than when levofloxacin was administered 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% in the presence of cimetidine and by 34% in the presence of probenecid. This is due to the ability of both drugs to block tubular secretion of levofloxacin. However, at the doses tested in clinical studies, statistically significant kinetic differences are unlikely to have clinical significance. Levofloxacin should be used with caution concomitantly with medicinal products affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other information

The following medicinal products have no clinically significant effect on the pharmacokinetics of levofloxacin when administered concomitantly: calcium carbonate, digoxin, glyburide, 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 tests (prothrombin time/international normalized ratio (INR)) and/or bleeding, which may be severe, have been reported. Therefore, in patients receiving vitamin K antagonists concomitantly, coagulation parameters should be monitored (see section "Special precautions for use").

MEDICINAL PRODUCTS THAT PROLONG THE QT INTERVAL

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

Other significant information

No effect of levofloxacin on the pharmacokinetics of theophylline (a 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 between Levaxela® and food has been observed; therefore, the drug can be taken independently of food intake.

Special precautions for use

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

Resistance risk

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

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

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

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

Prolonged, disabling and potentially irreversible serious adverse reactions

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

Tendinitis and tendon rupture

Inflammation and rupture of tendons (most commonly, but not limited to, the Achilles tendon), sometimes bilateral, may occur within 48 hours of starting levofloxacin treatment and may even occur several months after discontinuation of therapy. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, organ transplant recipients, patients receiving daily doses of 1000 mg, and those receiving concomitant corticosteroid therapy. Therefore, concomitant use with corticosteroids should be avoided.

If signs of tendinitis (e.g., painful swelling, inflammation) occur, levofloxacin therapy should be discontinued and alternative treatment considered. Appropriate management of the affected limb (e.g., immobilization) should be initiated. Corticosteroids should not be used if signs of tendinopathy are present.

Myoclonus

Cases of myoclonus have been reported in patients receiving levofloxacin (see section "Adverse reactions"). The risk of myoclonus is increased in elderly patients and in patients with renal impairment if the levofloxacin dose is not adjusted according to creatinine clearance. Levofloxacin should be discontinued immediately upon the first occurrence of myoclonus, and appropriate treatment initiated.

Aortic aneurysm and dissection, valvular regurgitation/insufficiency

Epidemiological studies suggest an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and of aortic and mitral valve regurgitation following fluoroquinolone use, especially in older individuals. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/functional insufficiency of any cardiac valve 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 treatments in patients with a personal or family history of aneurysm or congenital heart valve defects, or in patients with diagnosed aortic aneurysm and/or dissection or valvular heart disease, or in the presence of other risk factors or conditions that may predispose to:

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

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

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

Patients should seek immediate medical help if they develop acute dyspnea, sudden palpitations, or develop abdominal or lower limb edema.

Clostridium difficile-associated disease

Diarrhea, particularly severe, persistent, and/or with blood, occurring during or after treatment with levofloxacin (including several weeks after treatment) may be a symptom of Clostridium difficile-associated disease. The most severe form of this condition is pseudomembranous colitis (see section "Adverse reactions"). Therefore, physicians should consider the possibility of Clostridium difficile-associated disease in patients who develop severe diarrhea during or after treatment with levofloxacin. If Clostridium difficile-associated disease is suspected, levofloxacin should be discontinued immediately and appropriate treatment initiated without delay. Medicinal products that inhibit intestinal motility are contraindicated in this case.

Patients with seizure predisposition

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, it should be used with extreme caution in patients predisposed to seizures and in those receiving concomitant medications that lower the seizure threshold, such as theophylline (see section "Interaction with other medicinal products and other forms of interaction"). If a seizure occurs, levofloxacin should be discontinued (see section "Adverse reactions").

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or manifest glucose-6-phosphate dehydrogenase deficiency may be prone to hemolytic reactions during treatment with quinolone antibiotics. Therefore, if levofloxacin must be used, patients should be monitored for possible hemolysis.

Patients with renal impairment

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

Hypersensitivity reactions

Levofloxacin may cause serious, potentially fatal hypersensitivity reactions (e.g., from angioedema to anaphylactic shock), occasionally after the first dose (see section "Adverse reactions"). If hypersensitivity reactions occur, patients must discontinue levofloxacin, seek immediate medical attention, and initiate appropriate treatment.

Severe skin reactions

Severe skin reactions such as toxic epidermal necrolysis (TEN, 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, which 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 monitored closely. If signs or symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative treatment considered. Re-initiation of levofloxacin therapy is contraindicated in patients who have experienced a serious reaction such as Stevens-Johnson syndrome, TEN, or DRESS syndrome during prior treatment.

Blood glucose alterations

As with all quinolones, alterations in blood glucose levels, including both hypoglycemia and hyperglycemia, have been reported. Hyperglycemia occurs more frequently in elderly patients and typically in diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. Close monitoring of blood glucose levels is recommended in diabetic patients (see section "Adverse reactions").

If a patient reports disturbances in blood glucose levels, treatment should be discontinued immediately and alternative antibacterial therapy with non-fluoroquinolone agents considered.

Phototoxicity prevention

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

Patients receiving vitamin K antagonists

Due to the possible increase in coagulation parameters (prothrombin time/INR) and/or increased frequency of hemorrhagic complications in patients receiving levofloxacin in combination with a vitamin K antagonist (e.g., warfarin), coagulation tests should be monitored when these medicinal products are used concomitantly (see section "Interaction with other medicinal products and other forms of interaction").

Psychotic reactions

Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. Very rarely, these progressed to suicidal thoughts and self-harming behavior, sometimes after only a single dose of levofloxacin (see section "Adverse reactions"). If such reactions occur, levofloxacin should be discontinued immediately upon the first signs or symptoms, and patients should be advised to seek medical advice. Alternative antibacterial therapy with non-fluoroquinolone agents should be considered and appropriate measures taken. Caution is recommended when prescribing levofloxacin to patients with psychotic disorders or a history of psychiatric illness.

QT interval prolongation

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

• congenital or acquired 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);
• 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, fluoroquinolones, including levofloxacin, should be used with caution 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 or sensorimotor polyneuropathy leading to paresthesia, hyposthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones, including levofloxacin.

Patients who develop neuropathic symptoms such as pain, burning, tingling, numbness, or weakness during levofloxacin therapy should inform their physician before continuing treatment to prevent the development of potentially irreversible conditions (see section "Adverse reactions").

Hepatobiliary disorders

Cases of hepatic necrosis up to hepatic failure with fatal outcome have been reported with levofloxacin, primarily in patients with severe underlying conditions such as sepsis (see section "Adverse reactions"). Patients should be advised to discontinue treatment and consult a physician if symptoms of liver disease occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.

Exacerbation of myasthenia gravis

Fluoroquinolones, including levofloxacin, have neuromuscular blocking effects and may exacerbate muscle weakness in patients with myasthenia gravis. In the post-marketing period, serious adverse reactions including fatal cases and conditions requiring respiratory support have been associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances

If any visual disturbances or adverse reactions affecting the eyes occur during levofloxacin therapy, patients should seek immediate ophthalmological consultation (see sections "Ability to influence driving and use of machines" and "Adverse reactions").

Superinfection

The use of levofloxacin, especially prolonged use, may lead to overgrowth of organisms not susceptible (resistant) to the drug. If superinfection occurs during therapy, appropriate measures should be taken.

Effect on laboratory test results

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

Acute pancreatitis

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

Blood disorders

Treatment with levofloxacin may lead to bone marrow dysfunction, 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.

Levofloxacin may suppress the growth of Mycobacterium tuberculosis and thus may lead to false-negative results in bacteriological diagnosis of tuberculosis.

Excipients

The medicinal product Levaxela® contains the dye sunset yellow FCF (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding

Due to the lack of studies and the potential for quinolones to damage developing joint cartilage, levofloxacin is contraindicated during pregnancy and breastfeeding. If pregnancy is diagnosed during treatment with levofloxacin, this should be reported to the physician.

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

Ability to influence driving and use of machines

Levofloxacin has a minor or moderate influence on the ability to drive and use machinery.

Some adverse reactions (e.g., dizziness/vertigo, somnolence, visual disturbances) may impair a patient’s ability to concentrate and reaction speed, thereby increasing the risk in situations where these abilities are particularly important (e.g., driving a vehicle or operating machinery).

Dosage and Administration.

The drug should be taken once or twice daily. The dose depends on the type and severity of the infection. The duration of treatment depends on the course of the disease.

Levaxel tablets can also be used to complete the treatment course in patients who have shown improvement during initial intravenous therapy with levofloxacin; considering the bioequivalence of the parenteral and oral forms, the same dose may be used.

Table 3

Dosage for patients with normal renal function, in whom creatinine clearance is > 50 ml/min (depending on the severity of the infection)

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

Special patient groups

Table 4

Dosing for patients with impaired renal function in whom creatinine clearance ≤ 50 ml/min

Creatinine clearance	Dosing regimen (depending on severity of infection and nosology)
	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 (also during hemodialysis and CAPD)1	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 not impaired, dose adjustment is not required (see section "Special warnings and precautions for use" ("Tendinitis and tendon rupture" and "QT interval prolongation")).

Method of administration

Levaxel® tablets should be swallowed whole, without chewing, with sufficient fluid. For dose adjustment, tablets may be divided along the score line. Tablets may be taken during or between meals. Levaxel® tablets should be taken at least 2 hours before or after antacids containing iron, zinc salts, magnesium or aluminum, or didanosine (this applies only to didanosine formulations containing aluminum or magnesium buffering agents) or sucralfate, as these agents may reduce the absorption of levofloxacin (see section "Interaction with other medicinal products and other forms of interaction").

Children

Levofloxacin is contraindicated in children (under 18 years of age) because of the potential risk of damage to articular cartilage.

Overdose.

Symptoms

The most important expected symptoms of levofloxacin overdose involve the central nervous system: confusion, dizziness, altered consciousness, seizures, hallucinations, tremor, nausea, mucosal erosion, QT interval prolongation, as well as gastrointestinal reactions such as nausea and mucosal erosion.

In the post-marketing period, central nervous system symptoms have been observed, including confusion, seizures, myoclonus, hallucinations, and tremor.

Treatment

Treatment is symptomatic. Given the potential for QT interval prolongation, ECG monitoring should be performed. In cases of clear overdose, gastric lavage should be administered. Antacid agents may be used to protect the gastric mucosa. Hemodialysis, including peritoneal dialysis and continuous ambulatory peritoneal dialysis (CAPD), is ineffective in removing levofloxacin from the body. There is no specific antidote.

Adverse reactions.

The adverse reactions listed below are categorized by system organ and frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), frequency not known (frequency cannot be estimated based on available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Classes and systems	Common	Uncommon	Rare	Frequency unknown
Infections and infestations		Fungal infections, including infections caused by Candida species; resistance of pathogenic microorganisms
Blood and lymphatic system disorders		Leukopenia, eosinophilia	Thrombocytopenia, neutropenia	Disorders of bone marrow function, including aplastic anemia, pancytopenia, agranulocytosis, hemolytic anemia
Immune system disorders			Angioedema (Quincke's edema), hypersensitivity2	Anaphylactic shock1, anaphylactoid shock1,2
Endocrine disorders			Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition disorders		Anorexia	Hypoglycemia, especially in patients with diabetes mellitus; hypoglycemic coma2	Hyperglycemia2
Psychiatric disorders3	Insomnia	Anxiety, confusion, nervousness	Psychotic reactions (e.g., with hallucinations, paranoia); depression, agitation, sleep disturbances, nightmares, delirium	Psychotic disorders with patient-endangering behavior, including suicidal thoughts or suicide attempts2, mania
Nervous system disorders3	Headache, dizziness	Somnolence, tremor, dysgeusia	Seizures2,4, paresthesia, memory impairment	Peripheral sensory neuropathy2; peripheral sensory motor neuropathy; parosmia, including anosmia; dyskinesia, extrapyramidal disorders, ageusia, loss of consciousness, benign intracranial hypertension, myoclonus
Eye disorders3			Visual disturbances, such as blurred vision2	Transient loss of vision2, uveitis
Ear and labyrinth disorders3		Vertigo	Tinnitus	Hearing loss, worsening of hearing
Cardiac disorders5			Tachycardia, palpitations	Ventricular tachycardia, which may lead to cardiac arrest; ventricular arrhythmia and torsades de pointes (mainly observed in patients with risk factors for QT interval prolongation); QT interval prolongation as measured by ECG2,6
Vascular disorders5			Arterial hypotension
Respiratory, thoracic and mediastinal disorders		Dyspnea		Bronchospasm, allergic pneumonitis
Gastrointestinal disorders	Diarrhea, vomiting, nausea	Abdominal pain, dyspepsia, flatulence, constipation		Hemorrhagic diarrhea, which rarely may indicate enterocolitis, including pseudomembranous colitis2; pancreatitis2
Hepatobiliary disorders	Elevated liver enzymes (ALT/AST, alkaline phosphatase, GGT)	Elevated blood bilirubin levels		Jaundice and severe hepatic injury, including cases of fatal acute liver failure, primarily in patients with severe underlying diseases2; hepatitis
Skin and subcutaneous tissue disorders7		Rash, pruritus, urticaria, hyperhidrosis	Drug reaction with eosinophilia and systemic symptoms (DRESS)2, fixed drug eruption	Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, photosensitization reactions2, leukocytoclastic vasculitis, stomatitis, skin hyperpigmentation
Musculoskeletal and connective tissue disorders3		Arthralgia, muscle pain	Tendon disorders2,4, including tendinitis (e.g., Achilles tendon); muscle weakness, which may be significant in patients with myasthenia gravis2	Acute necrosis of skeletal muscles; tendon rupture (e.g., Achilles tendon)2,4; ligament rupture, muscle rupture, arthritis
Renal and urinary disorders		Elevated blood creatinine levels	Acute renal failure (e.g., due to interstitial nephritis)
General disorders and administration site conditions4		Asthenia	Pyrexia	Pain (including back, chest, limb pain)

1Anaphylactic and anaphylactoid reactions may sometimes occur even after administration of the first dose of the drug.

2See section "Special precautions for use".

3See section "Contraindications".

4Very rare cases of prolonged (for months or years), disabling and potentially irreversible serious adverse reactions have been reported with the use of quinolones and fluoroquinolones, sometimes affecting multiple body systems and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathy (associated with paresthesia and neuralgia), fatigue, psychiatric symptoms (including sleep disorders, anxiety, panic attacks, depression and suicidal thoughts), memory impairment, and worsening of hearing, vision, taste and smell), sometimes occurring regardless of the presence of risk factors (see section "Special precautions for use").

5Cases of aneurysm and aortic dissection, sometimes complicated by rupture (including fatal), and regurgitation/functional insufficiency of any heart valve have been reported in patients taking fluoroquinolones (see section "Special precautions for use").

6See section "Overdose".

7Skin and mucous membrane reactions may sometimes occur even after administration of the first dose of the drug.

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

Reporting of suspected adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions.

No special storage conditions are required for this medicinal product.

Keep out of the reach of children.

Packaging.

1 tablet in a blister; 1 blister in a cardboard box.

5 tablets in a blister; 1 or 2 blisters in a cardboard box.

7 tablets in a blister; 1 or 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia/KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and place of business.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia/Smarjeska cesta 6, 8501 Novo mesto, Slovenia.