Levaxela

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

Composition:

Active substance: levofloxacin;

1 ml of solution contains 5 mg of levofloxacin as levofloxacin hemihydrate;

Excipients: sodium chloride, hydrochloric acid concentrated, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: transparent greenish-yellow solution free from mechanical particles.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Fluoroquinolones. Levofloxacin.

ATC code J01MA12.

Pharmacological properties.

Pharmacodynamics.

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

Mechanism of action

Levofloxacin, as an antibacterial agent from the fluoroquinolone group, acts on the DNA gyrase and topoisomerase IV complex.

Pharmacokinetic/pharmacodynamic relationship

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

Mechanism of resistance

The primary mechanism of resistance is due to 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.

Clinical breakpoints

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

Table 1

Clinical MIC 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	≤ 1 mg/L	> 2 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 drug, at least for some types of infections, is questionable.

Commonly susceptible organisms

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

Aerobic gram-negative bacteria Eikenella corrodens, Haemophilus influenzae, Haemophilus para-influenzae, Klebsiella oxytoca, Moraxella catarrhalis, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri.

Anaerobic bacteria Peptostreptococcus.

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

Organisms 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.

Resistance mechanism of Staphylococcus aureus likely involves cross-resistance to fluoroquinolones, including levofloxacin.

Pharmacokinetics.

Absorption

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

Food has minimal effect on the absorption of levofloxacin.

Steady-state concentrations are reached 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 tissue penetration 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, with metabolites including desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the total drug 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 (over 85% of the administered dose). Mean total body 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 between oral and intravenous administration, indicating interchangeability of these routes.

Linearity

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

Special patient populations

Patients with renal impairment

Renal function impairment affects the pharmacokinetics of levofloxacin. In patients with impaired renal function, renal elimination is reduced and clearance is decreased, resulting in prolonged elimination half-life (see Table 2).

Table 2. Pharmacokinetics in renal impairment after a single oral 500 mg dose

Creatinine clearance (ml/min)	< 20	20-49	50-80
Renal clearance (ml/min)	13	26	57
Elimination 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 levofloxacin pharmacokinetics 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");
• chronic bacterial prostatitis;
• pulmonary form of anthrax: post-exposure prophylaxis and treatment (see section "Special precautions").

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

• community-acquired pneumonia;
• complicated skin and soft tissue infections.

Official recommendations on the 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 lactation.

Interaction with other medicinal products and other types of interactions.

Effect of other medicinal products on 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 the seizure threshold may occur with concomitant use of quinolones and theophylline, NSAIDs, or other medicinal products that lower the seizure threshold. Levofloxacin concentrations were approximately 13% higher in the presence of fenbufen 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 decreases by 24% with cimetidine and by 34% with probenecid. This is due to the ability of both drugs to inhibit tubular secretion of levofloxacin. However, at the doses tested in clinical studies, it is unlikely that these statistically significant kinetic differences would have clinical relevance. Levofloxacin should be used with caution in combination with medicinal products affecting tubular secretion, such as probenecid and cimetidine, especially in patients with impaired renal function.

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 elimination 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 parameters (prothrombin time/international normalized ratio (INR)) and/or bleeding events, which may be severe, have been reported. Therefore, coagulation parameters should be monitored in patients receiving concomitant vitamin K antagonists (see section "Special precautions").

MEDICINAL PRODUCTS THAT PROLONG THE QT INTERVAL

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

Other significant information

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

Special precautions for use

Levofloxacin should be avoided in patients who have previously experienced serious adverse reactions to drugs containing quinolone or fluoroquinolone (see section "Adverse reactions"). Treatment of these patients with levofloxacin should be initiated only if no alternative treatment options are available and after careful benefit-risk assessment (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 in cases where laboratory testing has confirmed susceptibility of the pathogen to levofloxacin.

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

Pulmonary anthrax

The use of the drug 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 consensus guidelines for the treatment of anthrax.

Prolonged, disabling, and potentially irreversible serious adverse reactions

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

Infusion duration

The recommended infusion duration should be at least 30 minutes for 250 mg or 60 minutes for 500 mg of levofloxacin infusion solution. Tachycardia and transient decrease in blood pressure may occur during ofloxacin infusion. Rarely, significant drop in blood pressure may lead to cardiovascular failure. If a marked drop in blood pressure occurs during levofloxacin (L-isomer of ofloxacin) infusion, administration of the drug should be stopped immediately.

Tendinitis and tendon rupture

Tendon inflammation and tendon rupture (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 treatment. 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 corticosteroids. Therefore, concomitant use with corticosteroids should be avoided.

At the first signs of tendinitis (e.g., painful swelling, inflammation), levofloxacin treatment should be discontinued and alternative therapy 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 and appropriate treatment initiated at the first occurrence of myoclonus.

Clostridium difficile-associated disease

Diarrhea, especially severe, persistent, and/or bloody diarrhea, 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 urgently. 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 when used concomitantly with medicinal products 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 predisposed to hemolytic reactions during treatment with quinolone antibiotics. Therefore, if levofloxacin must be used, patients 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 renal impairment (see section "Dosage and administration").

Hypersensitivity reactions

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

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 about the signs and symptoms of these severe skin reactions and closely monitored during treatment. If signs or symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative therapy considered. Re-initiation of levofloxacin treatment is prohibited in patients who have experienced a serious reaction such as Stevens-Johnson syndrome, TEN, or DRESS syndrome during previous treatment.

Blood glucose alterations

As with all quinolones, alterations in blood glucose levels, including both hypoglycemia and hyperglycemia, have been reported, with hyperglycemia being more common in elderly patients, usually in diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. Blood glucose levels should be closely monitored 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 during levofloxacin treatment (see section "Adverse reactions"). To prevent photosensitivity, patients should avoid exposure to strong sunlight or artificial UV radiation (e.g., artificial ultraviolet radiation, tanning beds) 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, coagulation tests should be monitored in patients receiving levofloxacin in combination with vitamin K antagonists (e.g., warfarin) (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-destructive behavior, sometimes after only a single dose of levofloxacin (see section "Adverse reactions"). If such reactions occur, levofloxacin should be discontinued immediately at 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. Levofloxacin should be used with caution in 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 QT prolongation syndrome;
• concomitant use of medicinal products capable of prolonging the QT interval (class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics);
• electrolyte imbalance (e.g., hypokalemia, hypomagnesemia);
• heart 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, hypoesthesia, 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 treatment should inform their physician before continuing treatment to prevent potentially irreversible damage (see section "Adverse reactions").

Hepatobiliary disorders

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

Exacerbation of myasthenia gravis

Fluoroquinolones, including levofloxacin, have neuromuscular blocking effects and may exacerbate muscle weakness in patients with myasthenia gravis. In post-marketing experience, serious adverse reactions, including fatalities 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 treatment, patients should seek immediate ophthalmological consultation (see sections "Effect on ability to drive and use machines" and "Adverse reactions").

Superinfection

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

Effect on laboratory test results

In patients receiving levofloxacin, urine opiate testing may yield false-positive results. Confirmation of positive opiate screening results may require more specific analytical methods.

Levofloxacin may inhibit the growth of Mycobacterium tuberculosis, potentially leading to false-negative results in bacteriological diagnosis of tuberculosis.

Aortic aneurysm and dissection, valvular regurgitation/insufficiency

Epidemiological studies suggest an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and aortic and mitral valve regurgitation following fluoroquinolone use, especially in older individuals. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal), and regurgitation/functional insufficiency of any heart valve have been reported in patients taking fluoroquinolones (see section "Adverse reactions").

Therefore, fluoroquinolones should be used only after careful benefit-risk assessment and consideration of alternative treatment options in patients with a family history of aneurysm or congenital heart valve defects, or in patients with diagnosed aortic aneurysm and/or dissection or heart valve 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 concurrently taking systemic corticosteroids.

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

Patients should seek immediate medical help if acute dyspnea, sudden palpitations, or development of abdominal or lower limb edema occurs.

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

During treatment with levofloxacin, bone marrow dysfunction 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.

Excipients

The medicinal product Levaxela® contains 354.20 mg of sodium in 100 ml of solution, which should be considered by patients on a salt-controlled diet.

Use during pregnancy or breastfeeding

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

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

Effect on ability to drive and use machines

Levofloxacin has a minor or moderate effect on the ability to drive and operate machinery. Some adverse reactions (e.g., dizziness/vertigo, somnolence, visual disturbances) may impair a patient's ability to concentrate and reaction speed, thereby increasing the risk in situations where these abilities are particularly important (e.g., driving vehicles or operating machinery).

Dosage and Administration

Levaxel® infusion solution is administered intravenously, slowly, 1–2 times daily. The dosage depends on the type and severity of infection, as well as on the susceptibility of the likely pathogen to the drug. Treatment with Levaxel® may be initiated intravenously and subsequently switched to an oral formulation, provided such a switch is appropriate for the individual patient. Due to the bioequivalence of parenteral and oral dosage forms, the same dose may be used.

Table 3

Dosage for patients with normal renal function, in whom creatinine clearance is > 50 mL/min

Indications	Dose, mg (depending on severity)	Number of doses per day	Duration of treatment1
Community-acquired pneumonia	500	1-2 times	7-14 days
Acute pyelonephritis	500	1 time	7-10 days
Complicated urinary tract infections	500	1 time	7-14 days
Chronic bacterial prostatitis	500	1 time	28 days
Complicated skin and soft tissue infections	500	1-2 times	7-14 days
Pulmonary form of anthrax	500	1 time	8 weeks

1The duration of treatment includes intravenous administration followed by oral therapy. The time to switch from intravenous to oral treatment depends on the clinical condition, but usually occurs between 2 and 4 days.

Special patient groups

Table 4

Patients with renal impairment in whom creatinine clearance is ≤ 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 normal, dose adjustment is not required.

Method of administration

Levaxel® infusion solution is intended only for slow intravenous administration; it is administered once or twice daily. The infusion duration should be at least 30 minutes for the 250 mg solution or 60 minutes for the 500 mg solution (see section "Special instructions").

Levaxel® infusion solution should be used immediately (within 3 hours) after perforation of the rubber stopper to prevent bacterial contamination. Protection from light is not required during infusion. The medicinal product is intended for single use only.

The solution should be inspected before use. Only a clear greenish-yellow solution free from particles should be used.

As with all other medicinal products, any unused medicinal product should be disposed of in accordance with local regulations.

Mixing with other infusion solutions:

Levaxel® infusion solution is compatible with the following infusion solutions:

• 0.9% sodium chloride solution;
• 5% glucose injection solution;
• 2.5% glucose in Ringer's solution;
• combined parenteral nutrition solutions (amino acids, glucose, electrolytes).

Information on incompatibilities is provided in the section "Incompatibilities".

Children.

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

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 including confusion, seizures, myoclonus, hallucinations, and tremor have been observed.

Treatment

In case of overdose, careful patient monitoring, including ECG, should be performed due to the potential for QT interval prolongation. Treatment is symptomatic. Hemodialysis, including peritoneal dialysis and continuous ambulatory peritoneal dialysis (CAPD), is ineffective in removing levofloxacin from the body. There are no specific antidotes.

Adverse reactions.

The adverse reactions listed below are categorized by system organ class and frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), frequency not known (cannot be estimated from the available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Systemic classes and classes	Common	Uncommon	Rare	Frequency not known
Infections and infestations		Fungal infections, including infections caused by Candida species; resistance of pathogenic microorganisms
Blood and lymphatic system disorders		Leukopenia, eosinophilia	Thrombocytopenia, neutropenia	Impairment of bone marrow function, including aplastic anemia, pancytopenia, agranulocytosis, hemolytic anemia
Immune system disorders			Angioedema, 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	Hypoglycemia2
Psychiatric disorders3	Insomnia	Anxiety, confusion, restlessness	Psychotic reactions (e.g., with hallucinations, paranoia); depression, agitation, sleep disturbances, nightmares, delirium	Psychotic disorders with behavior hazardous to the patient, 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 neuropathy2; parosmia, including anosmia; dyskinesia; extrapyramidal disorders; ageusia; loss of consciousness; benign intracranial hypertension, myoclonus
Eye disorders3			Visual disturbances, such as blurred vision2	Transient vision loss2, 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, recorded by ECG2, 6
Vascular disorders5	Applies only to intravenous administration: phlebitis		Arterial hypotension
Respiratory, thoracic and mediastinal disorders		Dyspnea		Bronchospasm, allergic pneumonitis
Gastrointestinal disorders	Diarrhea, vomiting, nausea	Abdominal pain, dyspepsia, flatulence, constipation		Hemorrhagic diarrhea, rarely may be a sign of enterocolitis, including pseudomembranous colitis2; pancreatitis2
Hepatobiliary disorders	Elevated liver enzymes (ALT/AST, alkaline phosphatase, GGT)	Elevated bilirubin levels in blood		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 myasthenia2	Acute skeletal muscle necrosis; tendon rupture (e.g., Achilles tendon)2,4; ligament rupture; muscle rupture; arthritis
Renal and urinary disorders		Elevated creatinine levels in blood	Acute renal failure (e.g., due to interstitial nephritis)
General disorders and administration site conditions4	Applies only to intravenous administration: infusion site reaction (pain, redness)	Asthenia	Pyrexia	Pain (including back, chest, limb pain)

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

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 organ systems and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathy (associated with paresthesia and neuralgia), fatigue, psychiatric symptoms (including sleep disorders, anxiety, panic attacks, depression and suicidal thoughts), memory impairment, and hearing, vision, taste and smell disturbances), 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 cases), and regurgitation/functional insufficiency of any heart valve have been reported in patients receiving 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 medicinal product.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization 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 through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Shelf life after perforation of the rubber stopper: immediate use (within 3 hours).

From a microbiological standpoint, the infusion solution should be used immediately. If use is delayed, responsibility for any deviation from recommended conditions of use and storage lies with the user.

Storage conditions.

Keep in the original packaging to protect from light. Keep out of the reach of children. During administration, the solution does not require protection from light.

Incompatibilities.

The medicinal product must not be mixed with infusion solutions and injections that are physically and chemically unstable at pH 3–4 (such as sodium bicarbonate, penicillin, heparin).

The medicinal product must not be mixed with other medicinal products in the same container, except as specified in the section "Dosage and administration".

Packaging.

100 ml of solution in a vial; 1, 5 or 10 vials per 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.

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