Levoaar

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

Composition:

Active ingredient: levofloxacin;

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

Excipients: maize starch, sodium croscarmellose, microcrystalline cellulose, purified talc, colloidal anhydrous silicon dioxide, sodium starch glycolate (type A), magnesium stearate, Opadry Yellow.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

250 mg tablets: light yellow, round, biconvex, film-coated tablets, smooth on both sides;

500 mg tablets: light yellow, oblong, film-coated tablets, with a score line on one side and smooth on the other.

Pharmacotherapeutic group

Antibacterial agents of the quinolone group. Fluoroquinolones.

ATC code J01M A12.

Pharmacological Properties

Pharmacodynamics

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

Mechanism of action. Levofloxacin, as an antibacterial agent of 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 maximum serum concentration (Cmax) or area under the pharmacokinetic curve (AUC) to the minimum inhibitory concentration (MIC).

Mechanism of resistance. Resistance to levofloxacin develops progressively due to mutations in the target site of type II topoisomerases, DNA gyrase, and topoisomerase IV. Other resistance mechanisms, such as penetration barriers (typical for Pseudomonas aeruginosa) and efflux mechanisms, may also affect susceptibility to levofloxacin.

Cross-resistance between levofloxacin and other fluoroquinolones is observed. Due to the mechanism of action, cross-resistance between levofloxacin and other classes of antibacterial agents is generally not observed.

Breakpoints

The recommended EUCAST (European Committee on Antimicrobial Susceptibility Testing) MIC breakpoints for levofloxacin, which differentiate susceptible microorganisms from those with intermediate susceptibility and those with intermediate susceptibility from resistant microorganisms, are presented in Table 1 for MIC testing (mg/L).

Table 1

EUCAST-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 spp.	≤ 0.001 mg/l	> 1 mg/l
Coagulase-negative staphylococci	≤ 0.001 mg/l	> 1 mg/l
Enterococcus spp.1	≤ 4 mg/l	> 4 mg/l
Streptococcus pneumoniae	≤ 0.001 mg/l	> 2 mg/l
Streptococcus A, B, C, G	≤ 0.001 mg/l	> 2 mg/l
Haemophilus influenzae	≤ 0.06 mg/l	> 0.06 mg/l
Moraxella catarrhalis	≤ 0.125 mg/l	> 0.125 mg/l
Helicobacter pylori	≤ 1 mg/l	> 1 mg/l
Aerococcus sanguinicola and urinae2	≤ 2 mg/l	> 2 mg/l
Aeromonas spp.	≤ 0.5 mg/l	> 1 mg/l
Pharmacokinetic-pharmacodynamic breakpoints (non-species related)	≤ 0.5 mg/l	> 1 mg/l

1Uncomplicated urinary tract infections.

2Susceptibility can be inferred based on sensitivity to ciprofloxacin.

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

Typically susceptible species

Aerobic Gram-positive bacteria

Bacillus anthracis, Staphylococcus aureus methicillin-susceptible, Staphylococcus saprophyticus, Streptococci, group C and G, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes.

Aerobic Gram-negative bacteria

Eikenella corrodens, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Moraxella catarrhalis, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri.

Anaerobic bacteria

Peptostreptococcus.

Others

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

Species for which acquired (secondary) resistance may be problematic

Aerobic Gram-positive bacteria

Enterococcus faecalis, Staphylococcus aureus methicillin-resistant*, coagulase-negative Staphylococcus spp.

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.

Inherently resistant strains

Aerobic Gram-positive bacteria

Enterococcus faecium.

*The resistance mechanism of Staphylococcus aureus is likely associated with cross-resistance to fluoroquinolones, including levofloxacin.

Pharmacokinetics

Absorption

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

Food has almost no effect on the absorption of levofloxacin.

Steady-state levels 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 about 100 L after 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, with metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the administered dose excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.

Elimination

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

Linearity

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

Special patient groups

Patients with renal impairment

Renal impairment affects the pharmacokinetics of levofloxacin. With reduced renal function, renal elimination and clearance decrease, and elimination half-life increases, as shown in Table 2 below:

Table 2

Pharmacokinetics in renal impairment after

a single oral dose of 500 mg

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

Geriatric Patients

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

Gender Differences

Separate analysis of female and male 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

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

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

The medicinal product should be used for the following infections only when it is considered inappropriate to use antibacterial agents usually recommended for initial treatment of these infections:

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

The medicinal product may also be used for completion of therapy in patients who have shown improvement during initial intravenous levofloxacin treatment.

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

Contraindications

• Hypersensitivity to levofloxacin, other fluoroquinolones, or to any component of the medicinal product;
• in patients with epilepsy;
• in patients with a history of tendon disorders related to fluoroquinolone administration;
• children and adolescents;
• pregnancy and breast-feeding.

Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on levofloxacin

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

The absorption of levofloxacin is significantly reduced when iron salts, magnesium- or aluminium-containing antacids, or didanosine (this applies only to medicinal forms of didanosine with aluminium- or magnesium-containing buffering agents) are administered concomitantly with the medicinal product. Concomitant administration of fluoroquinolones and multivitamin preparations containing zinc reduces their oral absorption. Medicinal 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 with aluminium- or magnesium-containing buffering agents) should not be administered within 2 hours before or after the medicinal product (see section "Method of administration and dosage"). 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 medicinal product (see section "Method of administration and dosage").

Theophylline, fenbufen, or similar non-steroidal anti-inflammatory drugs

No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a marked reduction in seizure threshold may occur when quinolones are used concomitantly with theophylline and non-steroidal anti-inflammatory drugs or other agents that reduce 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 because both medicinal products are capable of blocking tubular secretion of levofloxacin. However, at the doses tested in the study, it is unlikely that statistically significant kinetic differences would have clinical significance. Caution should be exercised when administering levofloxacin concomitantly with medicinal products affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other information

The following medicinal products do not cause any 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 administered concomitantly with vitamin K antagonists (e.g., warfarin), increased coagulation tests (prothrombin time/international normalized ratio) and/or bleeding, which may be severe, have been reported. Therefore, coagulation parameters should be monitored in patients receiving vitamin K antagonists concomitantly (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 (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, and antipsychotic medicinal products) (see section "Special precautions for use" (QT interval prolongation)).

Other significant information

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

Other types of interaction

Food intake

No clinically significant interaction with food has been observed. Therefore, the medicinal product can be administered independently of food intake.

Special Warnings and Precautions for Use

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

Prolonged, disabling, and potentially irreversible serious adverse reactions

In patients receiving quinolones and fluoroquinolones, very rare cases of prolonged (months or years), disabling, and potentially irreversible serious adverse reactions affecting various, sometimes multiple organ systems (musculoskeletal system, nervous system, psychiatric and sensory organs) have been reported, regardless of age or existing risk factors.

Treatment with levofloxacin must be discontinued immediately at the first signs or symptoms of any serious adverse reaction; patients should be advised to seek immediate medical consultation.

MRSA (Methicillin-resistant S. aureus)

For methicillin-resistant S. aureus (MRSA), there is a very high likelihood of cross-resistance to fluoroquinolones, including levofloxacin. 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 pathogen susceptibility to levofloxacin (and when the use of typically recommended antibacterial agents for MRSA infections is considered impossible).

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

Resistance to fluoroquinolones in E. coli (the most common cause of urinary tract infections) varies across countries. Local prevalence of fluoroquinolone resistance in E. coli should be considered 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 on the treatment of anthrax.

Tendinitis and tendon rupture

Tendinitis and tendon rupture (particularly of the Achilles tendon, but not limited to it), sometimes bilateral, may occur within 48 hours of starting treatment with quinolones and fluoroquinolones, and have been reported even several months after discontinuation of therapy. The risk of tendinitis and tendon rupture is higher in elderly patients, patients with impaired renal function, patients with solid organ transplants, and patients receiving doses of 1000 mg per day or concomitant corticosteroid therapy. Therefore, concomitant use of 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(s) (e.g., immobilization) should be ensured. Corticosteroids should not be used if signs of tendinopathy develop.

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 dose of levofloxacin is not adjusted according to creatinine clearance. Levofloxacin should be discontinued immediately at the first occurrence of myoclonus, and appropriate treatment initiated.

Clostridium difficile-associated disease

Diarrhea, especially severe, persistent, and/or bloody, 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 peristalsis are contraindicated in this case.

Patients with predisposition 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, 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 (see section "Adive Reactions"), levofloxacin should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency

Patients with latent or manifest deficiency in glucose-6-phosphate dehydrogenase activity may be prone to hemolytic reactions when treated with quinolone antibiotics. Therefore, if levofloxacin must be used in such patients, monitoring for possible hemolysis should be performed.

Patients with renal impairment

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

Hypersensitivity reactions

Levofloxacin may cause serious, potentially fatal hypersensitivity reactions (ranging from angioedema to anaphylactic shock), sometimes after the first dose. If hypersensitivity reactions occur, levofloxacin should be discontinued, medical advice sought, and appropriate treatment initiated.

Severe skin adverse reactions

Cases of severe skin adverse reactions (SCAR), including toxic epidermal necrolysis (TEN), also known as Lyell's syndrome, Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or fatal, have been reported. Patients should be informed about the signs and symptoms of severe skin reactions and closely monitored. If such signs and symptoms appear, levofloxacin should be discontinued immediately and alternative therapy considered. If a patient develops a serious reaction such as SJS, TEN, or DRESS while receiving levofloxacin, re-initiation of levofloxacin treatment in this patient is absolutely contraindicated.

Blood glucose alterations

As with other quinolones, cases of blood glucose disturbances, including both hypoglycemia and hyperglycemia, have been reported, usually in diabetic patients receiving concomitant therapy with oral hypoglycemic agents (e.g., glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. In diabetic patients, careful monitoring of blood glucose levels is recommended (see section "Adverse Reactions").

If blood glucose alterations occur in a patient, treatment with levofloxacin should be discontinued immediately, and alternative antibiotic therapy not belonging to the fluoroquinolone class should be considered.

Phototoxicity prevention

Cases of phototoxicity have been reported during treatment with levofloxacin (see section "Adverse Reactions"). To prevent phototoxicity, patients are advised to avoid exposure to strong sunlight or artificial UV radiation sources (e.g., UV lamps, 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/international normalized ratio) and/or increased frequency of hemorrhagic complications in patients receiving levofloxacin in combination with vitamin K antagonists (e.g., warfarin), coagulation parameters should be monitored when these agents are used concomitantly (see section "Interaction with other medicinal products and other forms of interaction").

Psychotic reactions

Psychotic reactions have been reported in patients receiving quinolones, including levofloxacin. Very rarely, these have led to suicidal thoughts and self-destructive behavior, sometimes even after 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 consult a physician. Alternative non-fluoroquinolone antibiotic therapy should be considered, and appropriate measures taken. Caution should be exercised when levofloxacin is prescribed 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 QT prolongation 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 conditions (e.g., heart failure, myocardial infarction, bradycardia) (see sections "Dosage and Administration (Elderly Patients)", "Interaction with other medicinal products and other forms of interaction", "Adverse Reactions", "Overdose").

Elderly patients and women may be more sensitive to drugs that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used cautiously in these patient groups.

Peripheral neuropathy

Cases of sensory or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. Patients taking levofloxacin should be advised to inform their physician before continuing treatment if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop, to prevent progression to potentially irreversible conditions.

Hepatobiliary disorders

Cases of liver necrosis up to liver failure with fatal outcome have been reported during treatment with levofloxacin (mainly in patients with severe underlying conditions such as sepsis) (see section "Adverse Reactions"). Patients should be advised to discontinue treatment and consult a physician if symptoms or signs of liver disease 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 ocular adverse reactions occur during levofloxacin treatment, patients should seek immediate consultation with an ophthalmologist (see sections "Adverse Reactions" and "Ability to affect driving and use of machines").

Superinfection

The use of levofloxacin, particularly prolonged use, may lead to overgrowth of organisms not susceptible (resistant) to the drug. If superinfection develops 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 may require more specific methods. Levofloxacin may inhibit the growth of Mycobacterium tuberculosis, potentially leading to false-negative results in bacteriological diagnosis of tuberculosis. Official guidelines on appropriate use of antibacterial agents should be considered.

Aortic aneurysm and dissection, valvular regurgitation/insufficiency

Epidemiological data suggest an increased risk of aortic aneurysm or dissection with fluoroquinolone use, particularly in elderly patients, and of aortic and mitral valve regurgitation following fluoroquinolone therapy. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and of 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 family history of aneurysm or congenital heart valve defect, or in patients with diagnosed aneurysm and/or aortic dissection, or heart valve disease, or in the presence of other risk factors or predisposing conditions:

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

The risk of aortic aneurysm, dissection, and 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 seek immediate medical help if acute dyspnea, new onset of 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 typical symptoms of acute pancreatitis. Patients experiencing nausea, malaise, abdominal discomfort, acute abdominal pain, or vomiting should undergo immediate medical evaluation. If acute pancreatitis is suspected, levofloxacin should be discontinued and not restarted if confirmed. Caution is advised in patients with a history of pancreatitis.

Blood disorders

During treatment with levofloxacin, bone marrow suppression may develop, including leukopenia, neutropenia, pancytopenia, hemolytic anemia, thrombocytopenia, aplastic anemia, or agranulocytosis (see section "Adverse Reactions"). If any of these disorders are suspected, blood test results should be monitored. If abnormal results are obtained, discontinuation of levofloxacin therapy should be considered.

Special warnings regarding inactive ingredients

The drug LEVOAAR contains the colorant sunset yellow FCF (E 110), which may cause allergic reactions.

This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., it is considered 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 with regard to reproductive toxicity. However, due to the lack of human studies and experimental data indicating a risk of fluoroquinolone-induced damage to the growing joint cartilage, levofloxacin is contraindicated during pregnancy.

Breastfeeding

Levofloxacin is contraindicated in women who are breastfeeding. Information on the passage of levofloxacin into breast milk is insufficient, although other fluoroquinolones are excreted in breast milk. Due to the lack of human studies and the potential for fluoroquinolones to damage the growing joint cartilage, levofloxacin should not be administered to women who are breastfeeding.

Fertility

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

Ability to affect driving and use of machines

Levofloxacin has a minor or moderate effect on the ability to drive or 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 or operating machinery).

Dosage and Administration

The medication should be taken once or twice daily. The dose depends on the type and severity of the infection and the susceptibility of the likely pathogen.

LEVОAAAR tablets may be used to complete the course of therapy in patients who have shown improvement during initial treatment with levofloxacin in infusion solution form, using the same dosage regimen, considering the bioequivalence of the parenteral and oral forms of the drug.

Table 3

Dosage for patients with normal renal function

(creatinine clearance over 50 mL/min)

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

Table 4

Dosage for patients with impaired renal function
(creatinine clearance less than 50 ml/min)

Creatinine clearance	Dosing regimen (depending on severity of infection and nosological form)
	250 mg/24 h	500 mg/24 h	500 mg/12 h
50–20 mL/min	initial dose – 250 mg, subsequent – 125 mg*/24 h	initial dose – 500 mg, subsequent – 250 mg/24 h	initial dose – 500 mg, subsequent – 250 mg/12 h
19–10 mL/min	initial dose – 250 mg, subsequent – 125 mg*/48 h	initial dose – 500 mg, subsequent – 125 mg*/ 24 h	initial dose – 500 mg, subsequent – 125 mg*/12 h
<10 mL/min (as well as during hemodialysis and CAPD**)	initial dose – 250 mg, subsequent – 125 mg*/48 h	initial dose – 500 mg, subsequent – 125 mg*/ 24 h	initial dose – 500 mg, subsequent – 125 mg*/24 h
*Since the tablet is not divisible, in cases where a dose lower than 250 mg is required, levofloxacin formulations allowing such dosing should be used. **Additional doses are not required after hemodialysis or continuous ambulatory peritoneal dialysis (CAPD).

Dosing in patients with hepatic impairment

Dose adjustment is not required, as levofloxacin is minimally metabolized in the liver and is primarily excreted via the kidneys.

Dosing in elderly patients

If renal function is normal, dose adjustment is not necessary (see section "Special precautions": tendinitis and tendon rupture, QT interval prolongation).

Method of administration

LEVOAAR tablets should be swallowed whole, without chewing, with sufficient fluid. The tablets may be taken with or without food. LEVOAAR 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 buffered with aluminum or magnesium), or sucralfate, since 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) due to the potential risk of damage to joint cartilage.

Overdose

Symptoms

Based on animal toxicity studies and clinical pharmacological data from administration of doses higher than therapeutic, the most significant expected signs following acute levofloxacin overdose include central nervous system (CNS) effects (confusion, dizziness, altered consciousness, and seizures); QT interval prolongation is possible; gastrointestinal reactions such as nausea and mucosal erosion. In the post-marketing period, CNS effects have been reported, including confusion, convulsions, myoclonus, hallucinations, and tremor.

Treatment

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

Adverse Reactions

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

System Organ 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	Bone marrow failure, including aplastic anemia, pancytopenia, agranulocytosis, hemolytic anemia
Immune system disorders			Angioedema, hypersensitivity	Anaphylactic shock, anaphylactoid shock
Metabolism and nutrition disorders		Anorexia	Hypoglycemia, especially in patients with diabetes mellitus, hypoglycemic coma	Hypoglycemia
Endocrine disorders			Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Psychiatric disorders*	Insomnia	Anxiety, confusion, nervousness	Psychotic reactions (e.g. with hallucinations, paranoia), depression, agitation, abnormal dreams, nightmares, delirium	Psychotic disorders with behavior hazardous to the patient, including suicidal thoughts or suicide attempts, mania
Nervous system disorders*	Headache, dizziness	Somnolence, tremor, dysgeusia (subjective taste disturbance)	Seizures, paraesthesia, memory impairment	Peripheral sensory neuropathy, peripheral sensory-motor neuropathy, parosmia (disturbance of smell), including anosmia (loss of smell), dyskinesia (disturbance of movement coordination), extrapyramidal disorders, ageusia, loss of consciousness, benign intracranial hypertension, myoclonus
Eye disorders*			Visual disturbances, such as blurred vision	Transient loss of vision, uveitis
Ear and labyrinth disorders*		Vertigo	Tinnitus	Hearing loss, worsening of hearing
Cardiac disorders**			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 ECG
Vascular disorders**			Arterial hypotension
Respiratory, thoracic and mediastinal disorders		Dyspnea		Bronchospasm, allergic alveolitis
Gastrointestinal disorders	Diarrhea, vomiting, nausea	Abdominal pain, dyspepsia, flatulence, constipation		Hemorrhagic diarrhea, which very rarely may be a sign of enterocolitis, including pseudomembranous colitis, pancreatitis
Hepatobiliary disorders	Elevated liver enzymes (ALT/AST, alkaline phosphatase, GGT)	Elevated blood bilirubin levels		Jaundice and severe liver damage, including cases of fatal acute liver failure, primarily in patients with severe underlying diseases, hepatitis
Skin and subcutaneous tissue disorders		Rash, pruritus, urticaria, hyperhidrosis	Drug reaction with eosinophilia and systemic symptoms (DRESS), persistent erythema multiforme	Toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, erythema multiforme, photosensitivity reactions, leukocytoclastic vasculitis, stomatitis, skin hyperpigmentation
Musculoskeletal and connective tissue disorders*		Arthralgia, muscle pain	Tendon disorders (see sections "Contraindications" and "Special warnings and precautions for use"), including tendinitis (e.g. Achilles tendon), muscle weakness which may be of particular importance in patients with myasthenia gravis (see section "Special warnings and precautions for use")	Acute skeletal muscle necrosis (rhabdomyolysis), tendon rupture (e.g. Achilles tendon) (see sections "Contraindications" and "Special warnings and precautions for use"), ligament rupture, muscle rupture, arthritis
Renal and urinary disorders		Elevated blood creatinine levels	Acute renal failure (e.g. due to interstitial nephritis)
General disorders*		Asthenia	Chills	Pain (including back, chest, limb pain)

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

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

Other adverse effects associated with fluoroquinolone use include:

• Acute attacks of porphyria in patients with known porphyria.

*In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of existing risk factors, have reported prolonged (lasting for months or years), disabling and potentially irreversible serious adverse reactions affecting different systems of the body and sensory organs, sometimes involving multiple systems simultaneously (including reactions such as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathy associated with paresthesia and neuralgia, fatigue, psychiatric symptoms (including sleep disturbances, anxiety, panic attacks, depression, and suicidal thoughts), memory and concentration impairment, and disturbances in hearing, vision, taste, and smell) (see section "Special precautions").

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, are encouraged to 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.

Storage conditions

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

Keep out of reach of children.

Packaging

250 mg strength: 6 or 10 film-coated tablets per blister. One blister per cardboard pack.

500 mg strength: 10 film-coated tablets per blister. One blister per cardboard pack.

Prescription status

Prescription only.

Manufacturer

Zim Laboratories Limited / Zim Laboratories Limited.

Manufacturer's address and location of operations

B-21/22, MIDC Area, Kalmeshwar, Nagpur, Maharashtra State, 441501, India /
B-21/22, MIDC Area, Kalmeshwar, Nagpur, Maharashtra State, 441501, India.