Levofloxacin

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

Composition:

Active ingredient: levofloxacin (levofloxacin);

1 tablet contains levofloxacin hemihydrate — 512.46 mg, equivalent to levofloxacin 500 mg;

Excipients: sodium stearyl fumarate, crospovidone, hypromellose, microcrystalline cellulose;

Coating: hypromellose, titanium dioxide (E 171), polyethylene glycol, yellow FCF aluminum lake (E 110), iron oxide red (E 172), iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: oval-shaped tablets, convex on both upper and lower surfaces, with a break line on one side, coated with a film coating ranging in color from light orange to orange.

Pharmacotherapeutic group. Antibacterial agents of the quinolone group. Fluoroquinolones.

ATC code J01MA12.

Pharmacological properties.

Pharmacodynamics.

Levofloxacin is a synthetic antibacterial agent belonging to the fluoroquinolone group and is 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 degree of antibacterial activity of levofloxacin depends on the ratio of the maximum serum concentration (C_max) or the area under the pharmacokinetic curve (AUC) to the minimum inhibitory concentration (MIC).
Mechanism of resistance development

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 permeability 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 observed.

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 intermediate from resistant microorganisms, are presented in Table 1 for MIC testing (mg/L).

Table 1

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

The prevalence of resistance in 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 doubts about the appropriateness of using the medicinal product, at least for certain types of infections.

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

Preclinical safety data

Preclinical data revealed no special hazard for humans (based on standard studies of acute toxicity, repeated-dose toxicity, carcinogenicity, and reproductive and developmental toxicity).

Levofloxacin did not cause impairment of fertility or reproductive function in rats; the only manifestation of toxicity was delayed fetal maturation.

Levofloxacin did not induce genetic mutations in bacteria or mammalian cells; however, in vitro, it caused chromosomal aberrations in Chinese hamster lung cells, associated with inhibition of topoisomerase II. In vivo tests (micronucleus test, sister chromatid exchange test, unscheduled DNA synthesis test, dominant lethal test) did not reveal genotoxicity.

Only at very high doses did levofloxacin show phototoxic potential in mice. In the photomutagenicity test, no genotoxic potential of levofloxacin was detected, and in the photocarcinogenicity study, it even reduced tumor development.

Like other fluoroquinolones, levofloxacin caused cartilage changes in rats and dogs (formation of vesicles and cavities). These effects were more pronounced in young animals.

Pharmacokinetics.

Absorption. When administered orally, levofloxacin is rapidly and almost completely absorbed; peak plasma concentrations (Cmax) are reached within 1–2 hours after administration. 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. It has been demonstrated that levofloxacin penetrates 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; metabolites include desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the total 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). 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 over the range of 50 mg to 1000 mg.

Patients with renal impairment. The pharmacokinetics of levofloxacin are affected by renal impairment. With reduced kidney function, renal excretion and creatinine clearance decrease, and elimination half-life increases (see Table 2).

Table 2

Pharmacokinetics in renal impairment

after a single oral dose of 500 mg

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

Gender. Separate analysis of male and female 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.

The medicinal product Levofloxacin is indicated for the treatment in adults of the following infections caused by microorganisms sensitive to levofloxacin (see sections "Pharmacological properties" and "Special precautions"):

• acute bacterial sinusitis;
• exacerbations of chronic obstructive pulmonary disease, including bronchitis;
• community-acquired pneumonia;
• complicated skin and soft tissue infections;
• uncomplicated cystitis (see section "Special precautions").

Levofloxacin should be used for treatment of the above-mentioned infections only when other antibacterial agents typically prescribed for initial treatment of these infections cannot be used.

• complicated urinary tract infections and acute pyelonephritis (see section "Special precautions");
• chronic bacterial prostatitis;
• pulmonary form of anthrax: post-exposure prophylaxis and treatment (see section "Special precautions").

Levofloxacin in this pharmaceutical form (film-coated tablets) may be used to complete the course of therapy in patients who have shown clinical improvement during initial treatment with levofloxacin intravenous infusion.

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 disorders related to fluoroquinolone administration.

Paediatric population.

Pregnancy and lactation.

Interaction with other medicinal products and other forms of interaction.

Effect of other medicinal products on levofloxacin

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

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

Calcium salts have minimal effect on the absorption of levofloxacin following oral administration.

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 taking levofloxacin tablets (see section "Dosage and administration").

Theophylline, fenbufen, or similar non-steroidal 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 and theophylline, NSAIDs, or 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 levofloxacin elimination. Renal clearance of levofloxacin is reduced by 24% in the presence of cimetidine and by 34% with probenecid. This is explained by the ability of both drugs to block tubular secretion of levofloxacin. However, at the doses tested in clinical studies, it is unlikely that statistically significant kinetic differences will have clinical relevance. Levofloxacin should be administered with caution together with medicinal products affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other medicinal products

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

Effect of levofloxacin on other medicinal products

Cyclosporine

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

Vitamin K antagonists

When administered concomitantly with vitamin K antagonists (e.g., warfarin), increased coagulation parameters (prothrombin time [PT]/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, as well as 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 "Special 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 forms of interaction

Corticosteroids

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

Food intake

No clinically significant interaction with food has been observed; therefore, Levofloxacin 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 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 in cases where laboratory testing has confirmed susceptibility of the pathogen to levofloxacin (and if use of antibiotics typically recommended 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 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.

Use of the medicinal product for pulmonary anthrax is based on in vitro susceptibility data for 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

Rare cases of prolonged (lasting for months or years), disabling, and potentially irreversible serious adverse reactions affecting one or more organ systems (musculoskeletal, nervous system, psychiatric, sensory organs) have been reported in patients receiving quinolones and fluoroquinolones, regardless of age or presence of risk factors. Levofloxacin must be discontinued immediately at 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 starting quinolone or fluoroquinolone therapy; cases have also been reported several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in elderly patients, patients receiving 1000 mg levofloxacin daily, patients with renal impairment, patients after solid organ transplantation, and patients receiving concomitant corticosteroid therapy. Therefore, concomitant therapy with corticosteroids should be avoided.

If first symptoms of tendinitis (e.g., painful swelling, inflammation) occur, levofloxacin treatment must 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 receiving levofloxacin (see section "Adverse reactions"). The risk of myoclonus is increased in elderly patients and in patients with renal impairment if the levofloxacin dose is not adjusted according to creatinine clearance. Levofloxacin should be discontinued immediately upon first occurrence of myoclonus, and appropriate treatment initiated.

Clostridium difficile-associated disease

Diarrhea, particularly severe, persistent, and/or hemorrhagic, occurring 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 levofloxacin therapy. If Clostridium difficile-associated disease is suspected or confirmed, the medicinal product should be discontinued immediately and appropriate treatment initiated without delay. Medicinal products that inhibit intestinal motility are contraindicated in this clinical situation.

Patients predisposed to seizures

Quinolones may lower the seizure threshold and provoke seizures. Levofloxacin is contraindicated in patients with a history of epilepsy (see section "Contraindications"). As with other quinolones, levofloxacin should be used with extreme caution in patients predisposed to seizures and in those receiving drugs 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 "Adverse 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 susceptible to hemolytic reactions during treatment with quinolone antibacterial agents; therefore, levofloxacin should be used with caution in such patients, and monitoring for possible hemolysis is required.

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 "Dosage and administration").

Hypersensitivity reactions

Levofloxacin may cause serious, potentially fatal hypersensitivity reactions (e.g., angioedema, 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 care.

Severe skin reactions

Severe skin 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 during levofloxacin therapy; these reactions may be life-threatening or fatal (see section "Adverse reactions"). Patients should be warned about the signs and symptoms of these severe skin reactions, and close monitoring should be maintained. If signs or symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative therapy considered. Re-administration of levofloxacin to a patient who has experienced a serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or DRESS syndrome is strictly prohibited.

Blood glucose alterations

Alterations in blood glucose levels (both hyperglycemia and hypoglycemia) have been reported with quinolone use, particularly in diabetic patients and elderly 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 therapy should be discontinued immediately and alternative non-fluoroquinolone antibiotic therapy considered.

Phototoxicity prevention

Cases of photosensitivity have been reported during levofloxacin therapy (see section "Adverse reactions"). To prevent photosensitivity, 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.

Patients receiving vitamin K antagonists

Due to possible increased coagulation test results (INR/PT) 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 receiving 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 must be discontinued immediately at the first signs or symptoms, and patients should be advised to consult their prescribing physician. Alternative non-fluoroquinolone antibacterial therapy should be considered, and appropriate measures taken. Levofloxacin should be used with caution in patients with psychiatric 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:

• 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", "Dosage and administration. Elderly patients", "Overdose", and "Adverse reactions").

Peripheral neuropathy

Cases of sensory and/or sensorimotor polyneuropathy leading to paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving 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 hepatic failure with fatal outcome have been reported during levofloxacin therapy (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 of liver disease occur, such as anorexia, jaundice, dark urine, pruritus, or abdominal pain.

Blood disorders

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

Exacerbation of myasthenia gravis

Fluoroquinolones, including levofloxacin, block neuromuscular transmission and may exacerbate muscle weakness in patients with myasthenia gravis. Serious adverse reactions, including fatal outcomes 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 visual organs occur, patients should consult an ophthalmologist immediately (see sections "Ability to affect reaction rate when driving or operating machinery" and "Adverse reactions").

Superinfection

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

Aortic aneurysm and dissection, cardiac valve 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. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and cardiac valve regurgitation/insufficiency 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 family history of aneurysm or congenital heart valve defects, 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 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 the emergency department if sudden abdominal, chest, or back pain occurs.

Patients should be advised to seek immediate medical help if acute dyspnea, new onset 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 typical symptoms of acute pancreatitis such as nausea, malaise, abdominal discomfort, severe abdominal pain, or vomiting. If such symptoms occur, the patient should consult a physician immediately. Levofloxacin should be discontinued if acute pancreatitis is suspected. The medicinal product must not be re-administered if the diagnosis is confirmed. Caution is advised in patients with a history of pancreatitis (see section "Adverse reactions").

Effect on laboratory tests

In patients receiving levofloxacin, opiate screening in urine may yield false-positive results. Positive opiate test results may require confirmation using more specific methods.

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

Excipients

The sodium content of one tablet of this medicinal product is less than 1 mmol (23 mg), i.e., it is practically sodium-free.

The medicinal product also contains the colorant aluminium lake of Yellow West FCF (E 110), 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 related to reproductive toxicity (see section "Pharmacological properties").

Due to the lack of human studies and the potential for quinolones to damage cartilage in the growing organism, levofloxacin is contraindicated in pregnant women and women who are breastfeeding (see sections "Contraindications" and "Pharmacological properties"). If pregnancy occurs during treatment, the physician should be informed.

Period of breastfeeding. Levofloxacin is contraindicated during breastfeeding. Information on excretion of levofloxacin in 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 cartilage in the growing organism, levofloxacin must not be administered to women who are breastfeeding (see section "Contraindications").

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

Ability to affect reaction rate when driving or operating machinery.

The medicinal product has negligible or moderate influence on the ability to drive and use machinery. Some adverse reactions (e.g., dizziness/vertigo, somnolence, visual disturbances) may impair the patient's ability to concentrate and react, potentially increasing risk in situations where these abilities are particularly important (e.g., driving or operating machinery).

Dosage and Administration

Levofloxacin tablets are taken once or twice daily. The dose depends on the type, severity of the infection, and the susceptibility of the likely pathogen.

Levofloxacin in this pharmaceutical form (film-coated tablets) 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 forms of the drug.

Levofloxacin tablets should be swallowed whole without chewing, with an adequate amount of liquid. For convenient dosing, the tablet may be divided along the score line. Tablets may be taken regardless of food intake.

The drug 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 forms of interaction").

Table 3

Recommended dosage for adult patients with normal renal function

(creatinine clearance >50 mL/min)

Special populations

Table 4

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

1 No additional doses are required after hemodialysis or continuous 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 by the kidneys.

Elderly patients. If renal function is normal, dose adjustment is not required (see section "Special warnings and precautions for use": 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 studies conducted with doses higher than therapeutic, the most significant expected signs following acute levofloxacin overdose include CNS symptoms (confusion, dizziness, altered consciousness, seizures); QT interval prolongation; and gastrointestinal reactions such as nausea and mucosal erosions.

In the post-marketing period, cases of CNS effects have been observed, including confusion, convulsions, myoclonus, hallucinations, and tremor.

Treatment. Treatment is symptomatic. ECG monitoring should be considered due to the potential for QT interval prolongation. Antacids should be used to protect the 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 (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), 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, night terrors, delirium; 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, memory impairment; 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 disorders), 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 that 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 (see section "Special warnings and precautions for use").

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 — toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, erythema multiforme, photosensitivity reactions (see section "Special warnings and precautions for use"), leukocytoclastic vasculitis, stomatitis, skin hyperpigmentation.

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

Description of selected adverse reactions

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

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

* With the 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 disturbances, neuropathies associated with paresthesia, neuralgia, depression, suicidal thoughts, anxiety, panic attacks, fatigue, memory impairment, difficulty concentrating, sleep disturbances, and disturbances of hearing, vision, taste, and smell), sometimes occurring independently 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").

Other adverse reactions associated with fluoroquinolone use include acute attacks of porphyria in patients with known porphyria.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: 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 the reach and sight of children.

Packaging.

10 tablets per blister, 1 or 10 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

JSC "Lubnifarm".

Manufacturer's address and place of business.

16 Barvinkova St., Lubny, Poltava region, 37500, Ukraine.