Levofloxacin-zdorov'ya

INSTRUCTIONS FOR MEDICAL USE|consumption| OF THE MEDICINAL PRODUCT LEVOFLOXACIN-ZDOROV'YA (LEVOFLOXACIN-ZDOROV'YE)

Composition:

Active substance: levofloxacin;

One tablet contains levofloxacin hemihydrate equivalent to 250 mg or 500 mg of levofloxacin;

Excipients: microcrystalline cellulose, maize starch, hypromellose, magnesium stearate, sodium croscarmellose, talc, crospovidone, titanium dioxide (E 171), tartrazine (E 102).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical|physico-chemical| properties: film-coated tablets of light yellow to yellow color, |film-coated|with| a biconvex surface. Two layers are visible in cross-section.

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

Pharmacological Properties

Pharmacodynamics. Levofloxacin is a synthetic antibacterial agent from the group of fluoroquinolones 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 (PK/PD) 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 through a stepwise process of mutations at the target sites in both types of type II topoisomerases, DNA gyrase and topoisomerase IV. Other resistance mechanisms, such as permeability barriers (common in Pseudomonas aeruginosa) and efflux mechanisms, may also affect susceptibility to levofloxacin.

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

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

EUCAST clinical MIC breakpoints for levofloxacin (version 10.0, 2020-01-01):

The prevalence of resistance may vary geographically and over time for individual species, and it is advisable to obtain local information on microbial resistance, especially when treating severe infections. If necessary, advice from a specialist should be sought when local resistance prevalence is such that the benefit of the drug, at least for some types of infections, is questionable.

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

Pharmacokinetics.

Absorption. After oral administration, levofloxacin is rapidly and almost completely absorbed; peak plasma concentrations are reached within 1–2 hours. Absolute bioavailability is 99–100%.

Food has minimal effect on the absorption of levofloxacin.

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

Distribution. Approximately 30–40% of levofloxacin is bound to serum proteins. The mean volume of distribution of levofloxacin is approximately 100 L after single and repeated 500 mg doses, indicating extensive tissue distribution throughout the body.

Penetration into body tissues and fluids. Penetration of levofloxacin into bronchial mucosa, bronchial secretions, lung tissue, alveolar macrophages, lung parenchyma, skin (bulla fluid), prostate tissue, and urine has been demonstrated. However, levofloxacin penetrates poorly into cerebrospinal fluid.

Biotransformation. Levofloxacin undergoes minimal metabolism. The metabolites are desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for <5% of the administered dose and are excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.

Elimination. Following oral and intravenous administration, levofloxacin is eliminated from plasma relatively slowly (elimination half-life (t½) is 6–8 hours). It is primarily excreted by the kidneys (>85% of the administered dose).

Mean total systemic clearance of levofloxacin after a single 500 mg dose was 175 ± 29.2 mL/min.
There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration, indicating interchangeability of these routes of administration.

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

Patients with renal impairment. The pharmacokinetics of levofloxacin are affected by the degree of renal impairment. With declining renal function, renal excretion and clearance decrease, and elimination half-life increases, as shown in the table below.

Pharmacokinetics in renal impairment after a single 500 mg oral dose:

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

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

Clinical characteristics.

Indications. The drug 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 drug should be used for the following infections only when it is considered inappropriate to use antibacterial agents usually recommended for treatment of these infections.

• Acute bacterial sinusitis.
  • Acute exacerbation of chronic obstructive pulmonary disease, including bronchitis.
  • Community-acquired pneumonia.
  • Complicated skin and soft tissue infections.
• Uncomplicated cystitis.

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

Contraindications. Hypersensitivity to levofloxacin/other quinolones or excipients, epilepsy, history of tendon disorders related to fluoroquinolone use. Not to be used in children or adolescents during growth period, as well as in women during pregnancy or breastfeeding.

Interaction with other medicinal products and other types of interactions.

Effect of other medicinal products on levofloxacin

Iron salts, zinc salts, antacids containing magnesium and aluminium, didanosine. Absorption of levofloxacin is significantly reduced when administered concomitantly with iron salts or antacids containing magnesium or aluminium, or didanosine (only for formulations containing aluminium or magnesium buffering agents). Concomitant administration of fluoroquinolones with multivitamins containing zinc leads to reduced oral absorption. It is not recommended to take medicinal products containing divalent or trivalent cations, such as iron salts, zinc salts, antacids containing magnesium or aluminium, or didanosine (only for didanosine formulations containing aluminium or magnesium buffering agents), within 2 hours before/after administration of levofloxacin tablets (see section "Dosage and administration"). Calcium salts had minimal effect on the oral absorption of levofloxacin.

Sucralfate. Bioavailability of levofloxacin 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 levofloxacin (see section "Dosage and administration").

Theophylline, fenbufen or similar non-steroidal anti-inflammatory drugs. No pharmacokinetic interaction between levofloxacin and theophylline has been observed. However, a significant reduction in the cerebral seizure threshold may occur with concomitant use of quinolones with theophylline, non-steroidal anti-inflammatory drugs, and other agents that reduce the seizure threshold. Levofloxacin concentration in the presence of fenbufen was approximately 13% higher than with levofloxacin alone.

Probenecid and cimetidine. Probenecid and cimetidine statistically significantly affect the elimination of levofloxacin. Renal clearance of levofloxacin is reduced in the presence of cimetidine (24%) and probenecid (34%). This occurs because both drugs can block tubular secretion of levofloxacin. Nevertheless, statistically significant kinetic differences are unlikely to have clinical significance. Levofloxacin should be prescribed with caution concomitantly with drugs affecting tubular secretion, such as probenecid and cimetidine, especially in patients with renal impairment.

Other significant information. It is known that no clinically significant effect on the pharmacokinetics of levofloxacin occurred when administered concomitantly with calcium carbonate, digoxin, glyburide, ranitidine.

Effect of levofloxacin on other medicinal products

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

Vitamin K antagonists. When administered concomitantly with vitamin K antagonists (e.g., warfarin), increased values of coagulation tests (INR/PT) and/or bleeding, 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 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 antipsychotics) (see section "Special precautions").

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

Other types of interactions

Food. No clinically significant interaction with food has been observed. Therefore, the drug can be taken regardless of food intake.

Special precautions for use. Avoid using the drug in patients who have previously experienced serious adverse reactions to quinolones and fluoroquinolones. Treatment with levofloxacin in such patients should be initiated only if no alternative treatment options are available and after careful benefit/risk assessment.

Resistance risks. For methicillin-resistant Staphylococcus aureus (MRSA), there is a very high likelihood of co-resistance to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for treatment of infections known or suspected to be caused by MRSA, except in cases where laboratory test results confirm susceptibility of the pathogen to levofloxacin (and use of standard antibacterial agents for MRSA infections is considered inappropriate).

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

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

Pulmonary form of anthrax. For pulmonary anthrax, use is based on in vitro susceptibility data for Bacillus anthracis and experimental animal data, as well as limited human use data. Physicians should consider national and/or international agreed recommendations for the treatment of anthrax.

Long-term, disabling, and potentially irreversible serious adverse reactions. In very rare cases, patients receiving quinolones and fluoroquinolones, regardless of age and presence of risk factors, have developed long-term (lasting several months or years), disabling, and potentially irreversible adverse reactions affecting various body systems (including musculoskeletal, nervous, psychiatric, and sensory organs). If any signs or symptoms of adverse reactions occur, the drug should be discontinued immediately and medical advice sought.

Tendinitis and tendon rupture. Tendinitis and tendon rupture (particularly, but not limited to, Achilles tendon), sometimes bilateral, may occur within 48 hours of starting levofloxacin treatment and even several months after discontinuation of levofloxacin. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with renal impairment, organ transplant recipients, and patients taking corticosteroids. Therefore, concomitant use of corticosteroids should be avoided. At the first signs of tendinitis (e.g., painful swelling, inflammation), levofloxacin should be discontinued and alternative therapy considered. Appropriate therapy for the affected limb(s) (e.g., immobilization) is required. Corticosteroids should not be used if signs of tendinopathy appear.

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

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

Patients prone to seizures. Quinolones may lower the seizure threshold and provoke seizures. Levofloxacin is contraindicated in patients with a history of epilepsy (see section "Contraindications") and, like other quinolones, should be used with extreme caution in patients prone to seizures or when used concomitantly with active substances that lower the seizure threshold, such as theophylline. In case of seizures (see section "Adverse reactions"), levofloxacin treatment 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 when treated with quinolone group antibacterial agents. Therefore, if levofloxacin is to be used in these patients, monitoring for possible hemolysis is required.

Patients with renal impairment. Since levofloxacin is primarily excreted by the kidneys, the dose should be adjusted in patients with impaired renal function.

Hypersensitivity reactions. Levofloxacin may cause serious, potentially fatal hypersensitivity reactions (e.g., angioedema up to anaphylactic shock), sometimes after administration of the first dose. In such cases, patients should discontinue treatment immediately and seek medical advice or call emergency services for appropriate emergency measures.

Severe skin adverse reactions. Development of severe skin adverse reactions, 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, has been reported. Patients should be warned about 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 during levofloxacin treatment, levofloxacin therapy should never be restarted in this patient.

Blood glucose level changes. Alterations in blood glucose levels (including both hyperglycemia and hypoglycemia) have been reported with quinolone use, particularly in diabetic patients receiving concomitant oral hypoglycemic agents (e.g., glyburide) or insulin. Cases of hypoglycemic coma have been reported. Blood glucose levels should be monitored in diabetic patients.

If glycemic control is disturbed, levofloxacin should be discontinued immediately and alternative antibacterial therapy without fluoroquinolones prescribed.

Phototoxicity prevention. Cases of photosensitivity have been reported with levofloxacin use. To prevent phototoxicity, patients are advised to avoid exposure to strong sunlight or artificial UV radiation sources (e.g., UV lamps, tanning beds) during treatment and for 48 hours after discontinuation of levofloxacin.

Patients receiving vitamin K antagonists. Due to possible increased coagulation test values (INR/PT) and/or bleeding in patients taking levofloxacin concomitantly with vitamin K antagonists (e.g., warfarin), coagulation tests should be monitored if these drugs are used concomitantly.

Psychotic reactions. Psychotic reactions have been reported in patients taking quinolones, including levofloxacin. In very rare cases, these progressed to suicidal thoughts and self-destructive behavior, sometimes after a single dose of levofloxacin. If any signs or symptoms of such reactions occur, the patient should discontinue levofloxacin immediately and consult their physician. In such cases, alternative therapy not including fluoroquinolones is recommended, and appropriate measures should be taken. Levofloxacin should be used with caution in patients with psychotic disorders or psychiatric history.

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

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

Elderly patients and women may be more sensitive to medicinal products that prolong the QT interval; therefore, caution is required when using fluoroquinolones, including levofloxacin, in these populations.

Peripheral neuropathies. 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 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 necrotizing hepatitis 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 signs and symptoms of liver disease such as anorexia, jaundice, dark urine, pruritus, or abdominal pain occur.

Exacerbation of myasthenia gravis. Fluoroquinolones, including levofloxacin, block neuromuscular transmission and may provoke muscle weakness in patients with myasthenia gravis. Serious adverse reactions identified in the post-marketing period, including fatal cases and need for 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 vision is impaired or any ocular effects occur, immediate consultation with an ophthalmologist is required (see sections "Ability to affect reaction rate when driving or operating machinery" and "Adverse reactions").

Superinfection. Use of levofloxacin, especially prolonged use, may lead to overgrowth of resistant microorganisms. If superinfection develops during therapy, appropriate measures should be taken.

Effect on laboratory tests. In patients receiving levofloxacin, urine opiate testing may yield false-positive results. Confirmation of positive opiate test results using more specific methods may be necessary.

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

Aneurysm and aortic dissection, and valvular regurgitation/insufficiency. Data suggest an increased risk of aortic aneurysm and dissection, particularly in elderly patients, and aortic and mitral valve regurgitation/insufficiency following fluoroquinolone use. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and valvular regurgitation/insufficiency have been reported in patients receiving fluoroquinolones (see section "Adverse reactions").

Thus, fluoroquinolones should be used only after careful benefit/risk assessment and consideration of alternative therapies in patients with a family history of aneurysm or congenital heart valve defects, or patients diagnosed with aortic aneurysm and/or aortic dissection, or with heart valve disease, or with other risk factors or predisposing conditions:

• for both aortic aneurysm and dissection, and valvular 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, known atherosclerosis, or Sjögren's syndrome) or additionally
• for valvular 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.

In case of sudden abdominal, chest, or back pain, patients should seek immediate medical attention at an emergency department.

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 the characteristic symptoms of acute pancreatitis. Patients who develop nausea, malaise, abdominal discomfort, acute abdominal pain, or vomiting should be examined immediately. If acute pancreatitis is suspected, levofloxacin should be discontinued; if diagnosis is confirmed, levofloxacin should not be restarted. Caution is required when treating patients with a history of pancreatitis.

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

Excipients. Tartrazine (E 102), contained in the drug, 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 regarding reproductive toxicity. However, due to the lack of human studies and experimental data indicating a risk of fluoroquinolone-induced damage to the weight-bearing joint cartilage in the growing organism, levofloxacin should not be administered to pregnant women (see section "Contraindications").

Breastfeeding. Levofloxacin is contraindicated in women who are breastfeeding. Information on the penetration of levofloxacin into breast milk is insufficient, although other fluoroquinolones are excreted in breast milk. Due to the lack of human studies and experimental data on the possible damage to the weight-bearing joint cartilage in the growing organism by fluoroquinolones, levofloxacin should not be administered to women who are breastfeeding (see section "Contraindications").

Fertility. It is known that levofloxacin did not cause fertility or reproductive function disorders in rats.

Ability to affect reaction rate when driving or operating machinery. The medicinal product 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 the patient's ability to concentrate and reaction speed, thus increasing the risk in situations where these qualities are particularly important (e.g., driving a car or operating machinery).

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

The drug may also be used to complete the course of therapy in patients who have shown improvement during initial intravenous levofloxacin treatment; considering the bioequivalence of parenteral and oral forms, the same dosage may be used.

Dosage. The following dosage recommendations may be provided for the drug:

Dosage in patients with normal renal function (creatinine clearance >50 ml/min).

Special populations.

Renal impairment (creatinine clearance ≤50 ml/min).

1After hemodialysis or chronic ambulatory peritoneal dialysis (CAPD), additional doses are not required.

2Since the tablet is not divisible, when prescribing the drug at a dose less than 250 mg, levofloxacin formulations allowing such dosing should be used.

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

Elderly patients. If renal function is normal, no dose adjustment is necessary (see section "Special precautions").

Method of administration. Tablets should be swallowed whole, without chewing, with sufficient liquid. Tablets may be taken during or between meals. The drug should be administered at least 2 hours before or after administration of iron salts, zinc salts, antacids containing magnesium or aluminum, or didanosine (only for didanosine formulations containing aluminum or magnesium buffering agents) and sucralfate, as absorption may be reduced (see section "Interaction with other medicinal products and other forms of interaction").

Children. The drug is contraindicated in children under 18 years of age.

Overdose. Based on toxicity studies in animals or clinical pharmacological studies conducted with doses higher than therapeutic, the most important signs expected after acute levofloxacin overdose include central nervous system effects such as confusion, dizziness, altered consciousness, and seizures, QT interval prolongation, as well as gastrointestinal reactions such as nausea and mucosal erosions.

During post-marketing use of levofloxacin, central nervous system effects have been observed, including confusion, seizures, myoclonus, hallucinations, and tremor.

In case of overdose, symptomatic treatment should be administered. ECG monitoring is required due to the potential for QT interval prolongation. Antacids may be used to protect gastric mucosa. Hemodialysis, including peritoneal dialysis and CAPD, is not effective for removing levofloxacin from the body. There are no specific antidotes.

Adverse reactions

The information below is based on data from clinical studies in over 8300 patients and extensive post-marketing experience with levofloxacin.

Frequency is defined according to the following convention: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency group, adverse reactions are listed in order of decreasing severity of manifestations:

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

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

* In patients who have received quinolones and fluoroquinolones, very rare cases of prolonged (several months or years) disability and potentially irreversible serious adverse reactions affecting various body systems have been reported. Such reactions include tendinitis, tendon rupture, arthralgia, limb pain, difficulty walking, neuropathies with concomitant paresthesia and neuralgia, fatigue, psychiatric symptoms (including sleep disturbances, anxiety, panic attacks, depression, and suicidal thoughts), impaired memory and concentration, as well as disturbances in hearing, vision, taste, and smell. In some cases, these reactions occurred in patients without risk factors (see section "Special precautions for use").

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

Other adverse reactions associated with the use of fluoroquinolones:

• Porphyria attacks in patients with porphyria.

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 tablets, pack of 10 in a blister pack in a carton or 500 mg tablets, pack of 7 or 10 in a blister pack in a carton.

Prescription status. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

LIMITED LIABILITY COMPANY "FARMEKS GROUP".

Manufacturer's address and place of business. Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenka Street, building 22.

(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA")

Ukraine, 08301, Kyiv region, city of Boryspil, Shevchenka Street, building 100.

(LIMITED LIABILITY COMPANY "FARMEKS GROUP")