Levobacid

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

Composition:

Active substance: levofloxacin;

One film-coated tablet contains levofloxacin hemihydrate 512.46 mg, equivalent to levofloxacin 500 mg;

Excipients: microcrystalline cellulose, hydroxypropylcellulose, crospovidone, magnesium stearate;

Film coating: hypromellose, FD&C Blue #2 aluminum lake, FD&C Yellow #6 aluminum lake (E 110), iron oxide red (E 172), polyethylene glycol, titanium dioxide (E 171), iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: orange-colored, elongated, biconvex tablets with a score line.

Pharmacotherapeutic group. Antibacterial agents of the quinolone group. Fluoroquinolones. ATC code J01MA12.

Pharmacological properties.

Pharmacodynamics.

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

Mechanism of action

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

Pharmacokinetic/pharmacodynamic relationship

The extent 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 development

Resistance to levofloxacin develops stepwise 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 its mechanism of action, cross-resistance between levofloxacin and other classes of antibacterial agents is generally not present.

Clinical 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 clinically defined MIC breakpoints for levofloxacin (version 2.0, 2012-01-01)

Organism	Susceptible	Resistant
Enterobacteriaceae	≤ 1 mg/l	> 2 mg/l
Pseudomonas spp.	≤ 1 mg/l	> 2 mg/l
Acinetobacter spp.	≤ 1 mg/l	> 2 mg/l
Staphylococcus spp.	≤ 1 mg/l	> 2 mg/l
S. pneumoniae 1	≤ 2 mg/l	> 2 mg/l
Streptococcus A, B, C, G	≤ 1 mg/l	> 2 mg/l
H. influenzae 2, 3	≤ 1 mg/l	> 1 mg/l
M. catarrhalis 3	≤ 1 mg/l	> 1 mg/l
Non-species related breakpoints 4	≤ 1 mg/l	> 2 mg/l

1. Breakpoints for levofloxacin related to high-dose therapy.

2. Possible low-level resistance to fluoroquinolones (ciprofloxacin MIC 0.12–0.5 mg/L) may occur, but there is no evidence of clinical significance of this resistance in respiratory tract infections caused by Haemophilus influenzae.

3. Strains with MIC values above the breakpoint are very rare or have not yet been reported. Susceptibility testing for any such isolate must be repeated, and if confirmed, the isolate should be referred to a reference laboratory. Until clinical efficacy is demonstrated for confirmed isolates with MICs above the current resistance breakpoint, such isolates should be considered resistant.

4. Breakpoints apply to oral doses of 500 mg × 1 to 500 mg × 2 and intravenous doses of 500 mg × 1 to 500 mg × 2.

The prevalence of resistance among individual species may vary geographically and over time; therefore, local data on resistance are highly important, especially when treating severe infections. Expert advice should be sought when local resistance prevalence raises uncertainty regarding the appropriateness of using this medicinal product, at least for certain types of infections.

Generally susceptible species

Aerobic gram-positive bacteria: Bacillus anthracis, Staphylococcus aureus methicillin-susceptible, Staphylococcus saprophyticus, Streptococcus groups 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 with possible acquired resistance

Aerobic gram-positive bacteria: Enterococcus faecalis, Staphylococcus aureus methicillin-resistant (high likelihood of co-resistance to fluoroquinolones, including levofloxacin), 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.

Naturally resistant strains

Aerobic gram-positive bacteria: Enterococcus faecium.

Pharmacokinetics.

Absorption

After oral administration, levofloxacin is rapidly and almost completely absorbed; maximum plasma concentration (Cmax) is reached within 1–2 hours after intake. Absolute bioavailability is 99–100%. Food intake slightly affects its absorption. Steady-state levels are achieved within 48 hours after administration of 500 mg once or twice daily.

Distribution

Approximately 30–40% of levofloxacin is bound to plasma proteins. The mean volume of distribution of levofloxacin is approximately 100 L after single and repeated 500 mg doses, indicating extensive distribution into body tissues.

Penetration into tissues and body fluids

Levofloxacin has been shown to penetrate into bronchial mucosa, epithelial lining fluid, alveolar macrophages, lung tissue, skin (vesicle content), prostate tissue, and urine. However, penetration of levofloxacin into cerebrospinal fluid is poor.

Metabolism

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

Elimination

After both oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life is 6–8 hours). Elimination occurs primarily via the kidneys (over 85% of the administered dose). The mean apparent total clearance of levofloxacin after a single 500 mg dose is 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 in the dose range of 50 to 1000 mg.

Patients with renal impairment

Renal impairment affects the pharmacokinetics of levofloxacin. With reduced kidney function, renal elimination and creatinine clearance decrease, and elimination half-life increases (see Table 2).

Table 2

Pharmacokinetics in renal impairment after a single oral 500 mg dose

Clcr [mL/min]	< 20	20–49	50–80
ClR [mL/min]	13	26	57
t1/2 [hours]	35	27	9

Geriatric Patients

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

Gender

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

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to levofloxacin:

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

(Levofloxacin should be used to treat the above-mentioned infections only when it is considered inappropriate to use antibacterial agents typically recommended for initial treatment of these infections.)

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

The medicinal product may also be used to complete a course of therapy in patients who have shown improvement during initial intravenous levofloxacin treatment. Official recommendations regarding appropriate use of antibacterial agents should be taken into account.

Contraindications.

• Hypersensitivity to levofloxacin, other fluoroquinolones, or to any component of the medicinal product.
• Epilepsy.
• History of tendon damage associated with fluoroquinolone use.
• Pediatric age.
• Pregnancy and breastfeeding.

Interaction with other medicinal products and other types of interactions.

Effects of other medicinal products on levofloxacin.

Iron salts, zinc salts, antacids containing magnesium and aluminum, didanosine.
Absorption of levofloxacin is significantly reduced when iron salts, magnesium- or aluminum-containing antacids, or didanosine (only formulations containing aluminum or magnesium buffering agents) are administered simultaneously with levofloxacin tablets. Concomitant administration of fluoroquinolones with multivitamin preparations containing zinc results in reduced oral absorption. Medicinal products containing divalent or trivalent cations, such as iron salts, zinc salts, antacids containing magnesium or aluminum, or didanosine (this applies only to didanosine formulations containing aluminum or magnesium buffering agents) should not be administered within 2 hours before or after taking levofloxacin tablets (see section "Method of administration and dosage").

Calcium salts have minimal effect on the absorption of orally administered levofloxacin.

Sucralfate.

The bioavailability of levofloxacin tablets is significantly reduced when administered concomitantly with sucralfate. If a patient requires both sucralfate and levofloxacin, it is preferable to take sucralfate 2 hours after taking levofloxacin tablets.

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

No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant reduction in seizure threshold may occur with concomitant administration of quinolones with theophylline, NSAIDs, and other agents that lower the seizure threshold. The concentration of levofloxacin was approximately 13% higher when administered with 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% in the presence of cimetidine and by 34% with probenecid. This is explained by the fact that 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 will have clinical significance. Levofloxacin should be administered with caution concomitantly with medicinal products affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other medicinal products.

No clinically significant effect on the pharmacokinetics of levofloxacin has been observed when levofloxacin was administered concomitantly with calcium carbonate, digoxin, glyburide, or ranitidine.

Effects 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 [PT]/international normalized ratio [INR]) and/or bleeding, which may be severe, have been reported. Therefore, coagulation parameters should be monitored in patients receiving concomitant vitamin K antagonists.

MEDICINAL PRODUCTS THAT PROLONG THE QT INTERVAL.

Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving medicinal products capable of prolonging the QT interval (e.g., class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, and antipsychotics) (see section "Precautions. QT interval prolongation").

Other important information.

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

Other types of interactions.

Corticosteroids.

The risk of tendinitis and tendon rupture is increased in patients receiving corticosteroids and levofloxacin concomitantly. Therefore, concomitant administration of corticosteroids with levofloxacin should be avoided.

Food intake.

No clinically significant interaction between levofloxacin and food has been observed; thus, tablets may be taken independently of food intake.

Special precautions for use.

Levofloxacin should not be used in patients who have previously experienced serious adverse reactions to quinolones or fluoroquinolones (see section "Adverse reactions"). Treatment with levofloxacin in such patients should be initiated only if no alternative treatment options are available and after careful assessment of the benefit-risk ratio (see section "Contraindications").

Methicillin-resistant S. aureus.

There is a very high likelihood of cross-resistance to fluoroquinolones, including levofloxacin, in methicillin-resistant S. aureus (MRSA). Therefore, levofloxacin is not recommended for the treatment of infections known or suspected to be caused by MRSA, except when laboratory testing confirms susceptibility of the pathogen to levofloxacin (and when 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 properly diagnosed. Resistance of E. coli (the most common causative agent of urinary tract infections) to fluoroquinolones varies across different countries. Local prevalence of E. coli resistance to fluoroquinolones should be taken into account when prescribing fluoroquinolones.

The use of the medicinal product for pulmonary anthrax is based on in vitro susceptibility data of Bacillus anthracis, animal experimental data, and limited human experience. Physicians should consider national and/or international guidelines for the treatment of anthrax.

Prolonged, disabling and potentially irreversible serious adverse reactions.

Very rare cases of prolonged (lasting for months or years), disabling and potentially irreversible serious adverse reactions affecting various, sometimes multiple, body systems (musculoskeletal, nervous system, psychiatric, sensory organs) have been observed in patients treated with quinolones and fluoroquinolones, regardless of age or presence of risk factors. Levofloxacin therapy must be discontinued immediately upon the first signs or symptoms of any serious adverse reaction, and medical advice should be sought.

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 initiating treatment with quinolones and fluoroquinolones; cases have been reported even several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in elderly patients, patients receiving 1000 mg of levofloxacin daily, patients with impaired renal function, patients after solid organ transplantation, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant corticosteroid therapy should be avoided.

If first symptoms of tendinitis (e.g., painful swelling, inflammation) occur, levofloxacin treatment should be discontinued and alternative therapy considered. The affected limb(s) should be appropriately managed (e.g., immobilization). Corticosteroids should not be used if signs of tendinopathy occur.

Dosage adjustment is required for elderly patients based on creatinine clearance. Elderly patients receiving levofloxacin should be closely monitored.

Myoclonus.

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

Clostridium difficile-associated disease.

Diarrhea, especially severe, persistent, and/or hemorrhagic, during or after treatment with levofloxacin (including several weeks after treatment) may be a symptom of Clostridium difficile-associated disease. The severity of Clostridium difficile-associated disease may range from mild to life-threatening; the most severe form is pseudomembranous colitis (see section "Adverse reactions"). Therefore, it is important to consider this diagnosis in patients who develop severe diarrhea during or after treatment with levofloxacin. If Clostridium difficile-associated disease is suspected or confirmed, the medicinal product should be discontinued immediately and appropriate treatment initiated without delay. Antiperistaltic medicinal products are contraindicated in this clinical situation.

Patients predisposed to seizures.

Quinolones may lower the seizure threshold and provoke seizures. Levofloxacin is contraindicated in patients with a history of epilepsy (see section "Contraindications"). As with other quinolones, levofloxacin should be used with extreme caution in patients predisposed to seizures and in those receiving 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.

Patients with glucose-6-phosphate dehydrogenase deficiency.

Patients with latent or manifest deficiency of glucose-6-phosphate dehydrogenase activity may be susceptible to hemolytic reactions during treatment with quinolone-class antibacterial agents; therefore, levofloxacin should be used with caution in such patients, and monitoring for possible hemolysis is recommended.

Patients with renal impairment.

Since levofloxacin is primarily excreted by the kidneys, dosage adjustment is required in patients with impaired renal function (renal insufficiency) (see section "Posology and method of administration").

Hypersensitivity reactions.

Levofloxacin may cause serious, potentially fatal hypersensitivity reactions (e.g., angioedema up to anaphylactic shock), occasionally after administration of the first dose (see section "Adverse reactions"). Patients should discontinue treatment immediately and seek medical advice or emergency medical help.

Severe skin reactions.

Severe skin adverse reactions, such as toxic epidermal necrolysis (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 signs and symptoms of these severe skin reactions, and close monitoring should be maintained during treatment. If signs or symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative therapy considered. Reinitiation of levofloxacin treatment is prohibited in patients who have experienced serious reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome during prior levofloxacin use.

Blood glucose alterations.

Alterations in blood glucose levels (both hyperglycemia and hypoglycemia) have been reported with quinolone use, particularly in diabetic patients receiving concomitant oral hypoglycemic agents (including glibenclamide) or insulin (see section "Adverse reactions"). Cases of hypoglycemic coma have been reported. Blood glucose levels should be monitored in diabetic patients. If blood glucose changes occur, levofloxacin treatment should be discontinued immediately, and alternative antibiotic therapy not belonging to the fluoroquinolone class should be considered.

Phototoxicity prevention.

Although phototoxicity is very rare with levofloxacin, patients are advised to avoid intense sunlight or artificial UV radiation (e.g., UV lamps, sunbeds) during treatment and for 48 hours after its discontinuation to prevent phototoxic reactions.

Patients receiving vitamin K antagonists.

Due to possible increased coagulation test results (INR/aPTT) and/or bleeding in patients taking levofloxacin concomitantly with vitamin K antagonists (e.g., warfarin), coagulation parameters should be monitored when these medicinal products are used together (see section "Interaction with other medicinal products and other forms of interaction").

Psychotic reactions.

Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. In very rare cases, these progressed to suicidal 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 and appropriate measures taken. The medicinal product should be used with caution in patients with a history of psychotic disorders or psychiatric illness.

QT interval prolongation.

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

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

Elderly patients and younger women may be more sensitive to medicinal products that prolong the QTc interval; therefore, caution is required when using fluoroquinolones, including levofloxacin, in these patient groups (see sections "Interaction with other medicinal products and other forms of interaction", "Posology and method of administration. Elderly patients", "Overdose", and "Adverse reactions").

Peripheral neuropathy.

Cases of sensory and sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients treated with quinolones and fluoroquinolones. To prevent development of potentially irreversible conditions, patients receiving levofloxacin who experience symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness should inform their physician before continuing treatment (see section "Adverse reactions").

Hepatobiliary disorders.

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

Exacerbation of myasthenia gravis.

Fluoroquinolones, including levofloxacin, block neuromuscular transmission and may exacerbate muscle weakness in patients with myasthenia gravis. Serious adverse reactions, including fatalities and need for respiratory support, have been reported in patients with myasthenia gravis during post-marketing use of fluoroquinolones. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances.

If visual disturbances or other effects on the eye occur, patients should seek immediate ophthalmological consultation (see sections "Ability to influence reaction rate when driving or operating machinery" and "Adverse reactions").

Superinfection.

With levofloxacin use, particularly prolonged, overgrowth of resistant microorganisms may occur. If superinfection develops during therapy, appropriate measures should be taken.

Aneurysm and dissection of the aorta, 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. 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 be used only 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 with valvular heart disease, or with other risk factors or predisposing conditions:

• for both aortic aneurysm and 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 and dissection and their rupture may be increased in patients receiving systemic corticosteroids concomitantly.

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

Patients should be advised to seek immediate medical help if acute dyspnea, new onset of palpitations, or development of abdominal or lower limb edema occurs.

Blood disorders.

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

Acute pancreatitis.

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

Effect on laboratory tests.

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

Levofloxacin inhibits the growth of Mycobacterium tuberculosis, potentially leading to false-negative bacteriological test results in patients with tuberculosis.

Important information on excipients.

The medicinal product contains lactose and therefore should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free".

The tablet film coating contains azo dyes, which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Pregnancy.

Data on the use of levofloxacin in pregnant women are limited. Animal studies do not indicate direct or indirect harmful effects in terms of reproductive toxicity.

Due to the lack of human studies and the potential for quinolones to damage the joint cartilage in a growing organism, levofloxacin is contraindicated in pregnant women and in women who breastfeed. If pregnancy occurs during treatment, the physician should be informed.

Breastfeeding period.

Levofloxacin is contraindicated during breastfeeding. Information on the excretion 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 joint cartilage in a growing organism, 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 influence reaction rate when driving or operating 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 car or operating machinery).

Dosage and Administration

The tablets are taken once or twice daily. The dosage depends on the type and severity of infection and on the susceptibility of the probable causative organism.

LEVOBACID may be used to complete the course of therapy in patients who have shown improvement during initial treatment with levofloxacin infusion solution, using the same dosage regimen, taking into account the bioequivalence of the parenteral and oral dosage forms of the medicinal product. Tablets should be swallowed whole, without chewing, with an adequate amount of liquid. For convenience, the tablet may be divided along the score line. Tablets may be taken regardless of food intake.

The medicinal product should be administered at least 2 hours before or after administration of iron salts, zinc salts, antacids containing magnesium or aluminum, didanosine (only for formulations containing aluminum or magnesium in buffering agents), and sucralfate (see section "Interaction with Other Medicinal Products and Other Types of Interactions").

Table 3

Recommended dosage for adult patients with normal renal function

(creatinine clearance >50 mL/min)

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

Special populations.

Table 4

Dosing for patients with renal impairment (creatinine clearance ≤ 50 ml/min)

	Dosing regimen (depending on the severity of infection and nosological form)
	250 mg/24 hours	500 mg/24 hours	500 mg/12 hours
Creatinine clearance	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 (as well as during hemodialysis and CAPD1)	subsequent – 125 mg/48 hours	subsequent – 125 mg/24 hours	subsequent – 125 mg/24 hours

1 No additional doses are required after hemodialysis or chronic ambulatory peritoneal dialysis (CAPD).

Patients with hepatic impairment. Dose adjustment is not necessary, since levofloxacin is minimally metabolized in the liver and is primarily excreted via the kidneys.

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

Children.

Levofloxacin is contraindicated in children, as damage to joint cartilage cannot be excluded (see section "Contraindications").

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 are central nervous system [CNS] effects (confusion, dizziness, altered consciousness, and seizures); QT interval prolongation is possible; gastrointestinal reactions such as nausea and mucosal erosions may also occur. In the post-marketing period, CNS effects have been reported, including confusion, seizures, myoclonus, hallucinations, and tremor.

Treatment.

Treatment is symptomatic. ECG monitoring should be considered due to the potential for QT interval prolongation. Antacids should be administered to protect gastric mucosa. Hemodialysis, including peritoneal dialysis or CAPD, is not effective in removing levofloxacin from the body. There are no specific antidotes.

Adverse Reactions

The frequency of adverse reactions listed below was determined according to the following criteria: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

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

Infections and infestations. Uncommon: fungal infections, including Candida species, microbial resistance.

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

Blood and lymphatic system disorders. Uncommon: leukopenia, eosinophilia. Rare: thrombocytopenia, neutropenia. Frequency not known: bone marrow depression, including aplastic anemia, pancytopenia, agranulocytosis, hemolytic anemia.

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

Metabolism and nutrition disorders. Uncommon: anorexia. Rare: hypoglycemia, mainly in patients with diabetes mellitus, hypoglycemic coma (see section "Special warnings and precautions for use"). Frequency not known: hyperglycemia (see section "Special warnings and precautions for use").
Psychiatric disorders. Common: insomnia. Uncommon: anxiety, confusion, restlessness. Rare: psychotic reactions (including hallucinations, paranoia), depression, agitation, unusual dreams, nightmares, delirium, memory impairment. Frequency not known: mania, psychotic reactions with self-destructive behavior, including suicidal ideation or actions (see section "Special warnings and precautions for use").

Nervous system disorders. Common: headache, dizziness. Uncommon: somnolence, tremor, dysgeusia (subjective taste disturbance). Rare: seizures (see sections "Contraindications" and "Special warnings and precautions for use"), paresthesia. Frequency not known: myoclonus, peripheral sensory or sensorimotor neuropathy (see section "Special warnings and precautions for use"), olfactory disturbances (parosmia), including anosmia (loss of smell), dyskinesia (movement coordination disorder), extrapyramidal disorders, ageusia, syncope (fainting), benign intracranial hypertension.

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

Ear and labyrinth disorders. Uncommon: vertigo. Rare: tinnitus. Frequency not known: hearing loss, disturbances of hearing.

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

Vascular disorders. Rare: arterial hypotension.

Respiratory system disorders. Uncommon: dyspnea (shortness of breath). Frequency not known: bronchospasm, allergic pneumonitis.

Gastrointestinal disorders. Common: diarrhea, vomiting, nausea. Uncommon: abdominal pain, dyspepsia, flatulence/bloating, constipation. Frequency not known: hemorrhagic diarrhea, which may indicate enterocolitis, including pseudomembranous colitis (see section "Special warnings and precautions for use"), pancreatitis.

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

Skin and subcutaneous tissue disorders. Uncommon: rash, pruritus, urticaria, hyperhidrosis. Rare: drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (see section "Special warnings and precautions for use"), persistent drug eruptions. Frequency not known: skin hyperpigmentation, toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, erythema multiforme, photosensitivity reactions (see section "Special warnings and precautions for use"), leukocytoclastic vasculitis, stomatitis.

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

Renal and urinary disorders. Uncommon: increased serum creatinine levels. Rare: acute renal failure (e.g., due to interstitial nephritis).

General disorders. Uncommon: asthenia. Rare: increased body temperature (pyrexia). Frequency not known: pain (including back, chest, and 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.

* With use of quinolones and fluoroquinolones, very rare cases of prolonged (lasting months or years), disabling, and potentially irreversible serious adverse reactions have been reported, sometimes affecting multiple organ systems and sensory organs (including such reactions as tendinitis, tendon rupture, arthralgia, limb pain, gait disturbance, neuropathies associated with paresthesia, depression, fatigue, memory impairment, sleep disorders, and disturbances of hearing, vision, taste, and smell), occasionally occurring independently of the presence of risk factors (see section "Special warnings and precautions for use").

** 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 warnings and precautions for use").

Description of selected adverse reactions

Among other adverse effects associated with fluoroquinolone use, acute attacks of porphyria have been observed in patients with known porphyria.

Anxiety, suicidal thoughts, panic attacks, neuralgia, and difficulty concentrating are potential manifestations of prolonged fluoroquinolone-associated adverse reactions, which may lead to loss of work capacity.

Reporting suspected adverse reactions

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

Shelf life. 5 years.

Storage conditions.

No special storage conditions required. Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 1 blister in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

FARMATEN SA

Manufacturer's address and location of operations.

Derwenakion 6, Pallini Attica, 15351, Greece