Levoftor solution for infusion 5mg/ml 100ml No. 1

Instructions Levoftor solution for infusion 5mg/ml 100ml No. 1

Composition

active ingredient: levofloxacin;

1 ml of solution contains levofloxacin hemihydrate, equivalent to levofloxacin 5 mg; excipients: sodium chloride, hydrochloric acid, sodium hydroxide, water for injections.

Dosage form

Solution for infusion.

Main physicochemical properties: Transparent solution, green-yellow in color, practically free from particles.

Pharmacotherapeutic group

Antibacterials of the quinolone group. Fluoroquinolones. ATX code J01M A12.

Pharmacological properties

Pharmacodynamics

Levofloxacin is a synthetic antibacterial agent from the fluoroquinolone group, the S-enantiomer of the racemic mixture of the drug ofloxacin. As an antibacterial agent from the fluoroquinolone group, levofloxacin acts on the DNA complex of DNA gyrase and topoisomerase IV. The main mechanism of resistance is the result of mutations in the gyr-A genes. In vitro, there is cross-resistance between levofloxacin and other fluoroquinolones.

Breakpoints. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommended MIC breakpoints for levofloxacin that distinguish susceptible from intermediately susceptible (moderately resistant) organisms and intermediately susceptible from resistant organisms are presented in Table 1 MIC testing (mg/L). EUCAST clinical MIC breakpoints for levofloxacin:

Table 1

1 Levofloxacin breakpoints refer to high-dose therapy.

2Low-level resistance to fluoroquinolones (ciprofloxacin MIC 0.12–0.5 mg/L) is possible, but there is no evidence that such resistance is of clinical significance in respiratory tract infections caused by H. influenzae.

3Strains with MIC values above the breakpoint between susceptible and intermediately susceptible (moderately resistant) strains are very rare or have not yet been reported. Identification and antimicrobial susceptibility testing on any such isolate should be repeated and, if confirmed, the isolate should be sent to an authorized laboratory. Until there is evidence of a clinical response for confirmed isolates with MICs above the current resistance breakpoint, they should be reported as resistant.

4Limit values for oral doses from 500 mg once to 500 mg twice daily and for intravenous doses from 500 mg once to 500 mg twice daily.

Antibacterial spectrum.

The prevalence of resistance for selected species may vary geographically and over time. Local information on resistance is desirable, especially when treating severe infections.

Typically susceptible species:

Aerobic Gram-positive bacteria:

Bacillus anthracis, Staphylococcus aureus* methicillin-sensitive, Staphylococcus saprophyticus, Streptococci - groups C and G, Streptococcus agalactiae, Streptococcus pneumoniae*, Streptococcus pyogenes*.

Aerobic Gram-negative bacteria:

Burkholderia cepacia**, Eikenella corrodens, Haemophilus influenzae*, Haemophilus para-influenzae*, Klebsiella oxytoca, Moraxella catarrhalis*, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri.

Anaerobic bacteria:

Peptostreptococcus.

Others:

Chlamydophila pneumoniae*, Chlamydophila psittaci, Chlamidia trachomatis, Legionella pneumophila*, Mycoplasma pneumoniae*, Mycoplasma hominis, Ureaplasma urealyticum. Species for which acquired (secondary) resistance may be a problem: Aerobic Gram-positive bacteria:

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

Aerobic Gram-negative bacteria:

Acinetobacter baumannii*, Citrobacter freundii*, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae*, Escherichia coli*, Klebsiella pneumoniae, Morganella morganii*, Proteus mirabilis*, Providencia stuartii, Pseudomonas aeruginosa*, Serratia marcescens*.

Anaerobic bacteria:

Bacteroides fragilis, Bacteroides ovatus**, Bacteroides thetaiotamicron**, Bacteroides vulgatus**, Clostridium difficile**.

Naturally resistant strains:

Aerobic Gram-positive bacteria: Enterococcus faecium.

*Clinical efficacy has been demonstrated for susceptible isolates in approved clinical indications. **Naturally moderate susceptibility.

Other data:

Hospital-acquired infections caused by Pseudomonas aeruginosa may require combination therapy.

Pharmacokinetics

Absorption.

There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration. After intravenous administration, the drug accumulates in the bronchial mucosa and bronchial secretions of lung tissue (the concentration in the lungs exceeds that in blood plasma), in urine. Levofloxacin penetrates poorly into the cerebrospinal fluid.

Distribution.

Approximately 30-40% of levofloxacin is bound to serum proteins. There is virtually no cumulative effect with repeated doses of levofloxacin 500 mg once daily. There is a small but predictable cumulative effect after doses of 500 mg twice daily. Steady state is reached within 3 days.

Penetration into bronchial mucosa, bronchial secretions of lung tissues. The maximum concentration of levofloxacin in bronchial mucosa and bronchial secretions of lungs after oral administration of 500 mg was 8.3 and 10.8 μg/ml, respectively. These values were achieved within 1 hour after taking the drug.

Penetration into lung tissue.

The maximum concentration of levofloxacin in lung tissue after oral administration of 500 mg was approximately 11.3 μg/g and was reached 4-6 hours after drug administration. The concentration in the lungs exceeds that in blood plasma. Penetration into blister contents (skin).

The maximum concentration of levofloxacin (4.0-6.7 μg/ml) in the blister contents was reached 2-4 hours after administration of the drug during 3 days of use at doses of 500 mg 1 or 2 times a day, respectively.

Penetration into cerebrospinal fluid.

Levofloxacin penetrates poorly into the cerebrospinal fluid.

Penetration into prostate tissue.

After administration of 500 mg levofloxacin once daily for 3 days, mean concentrations in prostate tissue reached 8.7 μg/g, 8.2 μg/g, and 2 μg/g at 2 hours, 6 hours, and 24 hours, respectively; the mean prostate/plasma concentration ratio was 1.84.

Concentration in urine.

The mean urinary concentrations 8-12 hours after single oral doses of 150 mg, 300 mg and 500 mg levofloxacin were 44 mg/L, 91 mg/L and 200 mg/L, respectively.

Biotransformation.

Levofloxacin is metabolized to a minor extent, the metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the drug excreted in the urine. Levofloxacin is stereochemically stable and does not undergo inversion of the choral structure.

Breeding.

After oral and intravenous administration, levofloxacin is eliminated from the blood plasma relatively slowly (half-life is 6-8 hours). It is excreted mainly by the kidneys (more than 85% of the administered dose).

There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration, indicating that these routes of administration are interchangeable. Linearity.

Levofloxacin has linear pharmacokinetics in the range of 50-600 mg.

Patients with renal failure.

The pharmacokinetics of levofloxacin are affected by renal insufficiency. With decreased renal function, renal excretion and clearance are reduced, and the half-life is increased, as shown in Table 2.

Table 2

Elderly patients.

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

Separate analyses of male and female patients demonstrated slight gender differences in the pharmacokinetics of levofloxacin. There is no evidence that these gender differences in pharmacokinetics are clinically relevant.

Indication

Levoftor, solution for infusion, is indicated for the treatment of the following infectious diseases in adults:

− community-acquired pneumonia*;

− complicated skin and soft tissue infections*;

− acute pyelonephritis and complicated urinary tract infections;

− chronic bacterial prostatitis;

− pulmonary form of anthrax: post-exposure prophylaxis and radical treatment.

*For the above infectious diseases, levofloxacin should be prescribed only in cases of insufficient effectiveness of other antibacterial drugs, which are mainly used for the initial treatment of these infections.

Official recommendations on the appropriate use of antibacterial agents should be considered.

Contraindication

- Hypersensitivity to levofloxacin, to other quinolones or to any component of the drug.

− Adverse reactions from tendons after previous use of quinolones.

− Epilepsy.

− Childhood (up to 18 years old).

− Pregnancy or breastfeeding.

Interaction with other medicinal products and other types of interactions

Theophylline, fenbufen or similar non-steroidal anti-inflammatory drugs (NSAIDs). A significant decrease in the seizure threshold may occur when quinolones are used concomitantly with theophylline, NSAIDs and other substances that lower the seizure threshold. Levofloxacin concentrations in the presence of fenbufen are approximately 13% higher than when levofloxacin is administered alone.

Probenecid and cimetidine.

Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin. The renal clearance of levofloxacin is reduced by 34% in the presence of probenecid and by 24% in the presence of cimetidine. Therefore, both drugs are capable of blocking the tubular excretion of levofloxacin. They should be used with caution in patients with renal insufficiency.

Cyclosporine.

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

When used simultaneously with vitamin K antagonists (e.g. warfarin), coagulation test values (PT/international normalized ratio) increase. Severe bleeding is possible. Therefore, coagulation parameters should be monitored in patients receiving vitamin K antagonists in parallel.

Drugs that prolong the QT interval.

Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs that prolong the QT interval (including antiarrhythmics of classes IA and III, tricyclic antidepressants, macrolides, antipsychotics). Theophylline.

Levofloxacin does not affect the pharmacokinetics of theophylline, which is predominantly metabolized by CYP1A2, therefore it can be assumed that levofloxacin is not a CYP1A2 inhibitor.

Glucocorticoids.

Concomitant use with glucocorticoids increases the risk of tendon rupture.

Other.

No clinically significant effect on the pharmacokinetics of levofloxacin was observed when it was used together with the following drugs: calcium carbonate, digoxin, glibenclamide, ranitidine. The use of levofloxacin simultaneously with alcohol is not recommended.

Application features

The drug should be avoided in patients who have had serious adverse reactions to quinolones or fluoroquinolones in the past. Levofloxacin should only be initiated in these patients if no alternative treatment options are available and after a careful benefit/risk assessment.

Prolonged, disabling and potentially irreversible serious adverse reactions. In very rare cases, prolonged (months or years) disabling and potentially irreversible serious adverse reactions affecting different, and sometimes several, body systems (musculoskeletal, nervous, mental and sensory) have been reported in patients treated with fluoroquinolones, regardless of age and existing risk factors. The drug should be discontinued immediately at the first signs or symptoms of any serious adverse reaction and a doctor should be consulted.

Patients with severe renal impairment, as well as severe cerebral atherosclerosis and cerebrovascular disorders should be careful when using the drug. During the entire course of treatment, it is necessary to monitor kidney and liver function. When using the drug, you should refrain from drinking alcohol. In very severe pneumonia caused by pneumococci, levofloxacin may not have an optimal therapeutic effect. Hospital infections caused by Pseudomonas aeruginosa may require combination therapy.

Duration of administration. The recommended duration of administration of the medicinal product is at least 60 minutes for 500 mg of the infusion solution. With ofloxacin, tachycardia and a transient increase in blood pressure are known to occur during infusion. In rare cases, a sudden decrease in blood pressure, circulatory collapse may occur. If a pronounced decrease in blood pressure is observed during the administration of levofloxacin, the administration of the medicinal product should be stopped immediately. Aortic aneurysm and dissection and heart valve regurgitation/insufficiency Epidemiological studies have reported an increased risk of aortic aneurysm and dissection, especially in elderly patients, and of aortic and mitral valve regurgitation after the use of fluoroquinolones. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any of the heart valves have been reported in patients receiving fluoroquinolones (see section 4.8). Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with a positive family history of aneurysm or congenital heart valve disease, or in patients with an existing diagnosis of aortic aneurysm and/or dissection, or heart valve disease, or in the presence of other risk factors or predisposing conditions:

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

§ in case of regurgitation/valvular insufficiency (e.g. infective endocarditis). The risk of aortic aneurysm and dissection and their rupture may be increased in patients receiving concomitant systemic corticosteroids.

Methicillin-resistant Staphylococcus aureus (MRSA). Methicillin-resistant Staphylococcus aureus is likely to be cross-resistant to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of known or suspected MRSA infections unless laboratory testing has confirmed susceptibility to levofloxacin.

E. coli resistance. The resistance of E. coli, the most common cause of urinary tract infections, to fluoroquinolones varies across the European Union. When prescribing levofloxacin, physicians should take into account the local prevalence of fluoroquinolone resistance in E. coli.

Pulmonary anthrax. Clinical practice is based on in vitro susceptibility studies of Bacillus anthracis and experimental animal data together with limited human data. Physicians should use agreed national and/or international guidelines for the management of anthrax.

Tendinitis and tendon rupture. Tendinitis and tendon ruptures (not limited to the Achilles tendon), sometimes bilateral, may occur as early as 48 hours after initiation of treatment with quinolones and fluoroquinolones and even up to several months after discontinuation of treatment in patients receiving daily doses of 1000 mg levofloxacin. The risk of tendonitis and tendon rupture is increased in elderly patients, patients with impaired renal function, patients with solid organ transplantation and patients receiving concomitant corticosteroids. Therefore, concomitant use of the medicinal product with corticosteroids should be avoided. At the first sign of tendinitis (e.g. painful swelling, inflammation), treatment should be discontinued and alternative treatment considered. The affected limb(s) should be treated appropriately (e.g. by immobilization). Corticosteroids should not be used if there is evidence of tendinopathy.

Clostridium difficile infection. Diarrhoea, particularly severe, persistent or bloody during or after treatment with levofloxacin, may be a symptom of Clostridium difficile infection, the most severe form of which is pseudomembranous colitis. If pseudomembranous colitis is suspected, levofloxacin should be discontinued immediately and appropriate treatment (e.g. vancomycin) should be initiated immediately. Drugs that inhibit intestinal motility are contraindicated in this clinical situation. Patients with a predisposition to seizures. Quinolones may lower the seizure threshold and precipitate seizures. Levofloxacin is contraindicated in patients with a history of epilepsy. As with other quinolones, the drug should be used with extreme caution in patients prone to seizures, such as patients with central nervous system damage, during concomitant therapy with fenbufen and similar drugs or drugs that increase seizure susceptibility (lower the seizure threshold), such as theophylline (see section "Interaction with other medicinal products and other types of interactions"). In the event of seizures, treatment with levofloxacin should be discontinued.

Glucose-6-phosphate dehydrogenase deficiency: Patients with latent or advanced glucose-6-phosphate dehydrogenase deficiency are prone to hemolytic reactions when treated with quinolone antibacterial drugs, therefore levofloxacin should be used with caution in such patients due to the possibility of hemolysis.

Renal impairment: Since levofloxacin is excreted primarily by the kidneys, dose adjustment is required in patients with renal impairment (see section 4.2).

Hypersensitivity reactions: Levofloxacin may occasionally cause serious, potentially fatal hypersensitivity reactions (e.g. angioedema, anaphylactic shock), even after the first administration. If hypersensitivity reactions occur, levofloxacin should be discontinued, a doctor should be consulted and appropriate treatment should be initiated.

Severe bullous reactions. Severe cutaneous adverse reactions (SCARs), including toxic epidermal necrolysis (TEN), also known as Lyell syndrome, Stevens-Johnson syndrome (SJS), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported and can be life-threatening or fatal. Patients should be advised of the signs and symptoms of severe skin reactions and monitored closely. If such signs and symptoms occur, levofloxacin should be discontinued immediately and alternative treatment considered. If a patient has developed a serious reaction such as SJS, TEN or DRESS with levofloxacin, levofloxacin should never be restarted in that patient. Patients should be advised to seek immediate medical attention before continuing treatment if skin and/or mucous membrane reactions occur.

Prevention of photosensitivity reactions: Photosensitivity reactions have been reported during treatment with levofloxacin. To prevent photosensitivity reactions, patients taking levofloxacin should avoid sunlight and UV rays (artificial ultraviolet lamps, tanning beds) while taking levofloxacin and for 48 hours after stopping levofloxacin.

In patients taking vitamin K antagonists, blood coagulation parameters should be monitored when levofloxacin and vitamin K antagonists (warfarin) are co-administered due to the potential risk of increased blood coagulation parameters (prothrombin time/INR) and/or bleeding.

Psychotic reactions. Psychotic reactions have been reported in patients receiving quinolones, including levofloxacin. In very rare cases, these have progressed to suicidal ideation and self-harm, sometimes after only a single dose of levofloxacin. If a patient experiences these reactions, levofloxacin should be discontinued and appropriate measures should be taken. Levofloxacin should be used with caution in patients with psychotic disorders and in patients with a history of psychiatric illness.

QT prolongation: Cases of QT prolongation have been reported with fluoroquinolones. Caution should be exercised when administering fluoroquinolones, including levofloxacin, to patients with known risk factors for QT prolongation:

− congenital or acquired long QT syndrome;

− simultaneous use of drugs that prolong the QT interval (including antiarrhythmic drugs of classes IA and III, tricyclic antidepressants, macrolides, antipsychotic drugs);

− electrolyte imbalance (including hypokalemia, hypomagnesemia);

− heart disease (heart failure, myocardial infarction, bradycardia). Elderly patients are more sensitive to drugs that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used with caution in this group of patients.

Peripheral neuropathy: Cases of sensory or sensorimotor polyneuropathy resulting in paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients treated with quinolones and fluoroquinolones. Patients should be advised to inform their physician if they experience symptoms of neuropathy, such as pain, burning, tingling, numbness, or weakness, to prevent the development of a potentially irreversible condition.

Hepatobiliary disorders: Cases of hepatic necrosis, up to life-threatening hepatic failure, have been reported with levofloxacin, predominantly in patients with severe underlying diseases such as sepsis (see section 4.8). Patients should be advised to discontinue treatment and consult a physician if signs 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 induce muscle weakness in patients with myasthenia gravis. Serious adverse reactions, including fatalities and the need for respiratory support, have been reported post-marketing with fluoroquinolones in patients with myasthenia gravis. Levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

Visual disturbances: If visual disturbances or other effects on the eyes are observed, an ophthalmologist should be consulted immediately.

Superinfection: The use of levofloxacin, especially for a long time, may lead to excessive growth of microorganisms that are not susceptible to the drug. If superinfection develops during therapy, appropriate measures should be taken.

Laboratory effects: In patients receiving levofloxacin, urine tests for opiates may give false-positive results. Positive results for opiates may need to be confirmed by more specific methods. Levofloxacin may inhibit the growth of Mycobacterium tuberculosis, and false-negative results may occur in bacteriological tests in patients with tuberculosis.

Important information about excipients.

This medicinal product contains 860 mg/dose of sodium. Caution should be exercised when administering the product to patients on a controlled sodium diet.

Use during pregnancy or breastfeeding

Due to the lack of studies and the possible damage of quinolones to articular cartilage in a growing body, the drug is contraindicated during pregnancy and breastfeeding. If pregnancy occurs while using the drug, the doctor should be informed.

Levofloxacin did not cause impaired fertility or reproductive function in animals.

Ability to influence reaction speed when driving vehicles or other mechanisms

Some adverse reactions (e.g. dizziness/vertigo, drowsiness, visual disturbances) may impair the patient's ability to concentrate and react quickly and thus pose an increased risk in situations where these qualities are of particular importance (e.g. when driving or using machinery).

Method of administration and doses

The dosage depends on the type and severity of the infection, as well as the sensitivity of the possible pathogen to the drug.

The drug should be administered slowly intravenously 1-2 times a day by drip infusion. The duration of administration of 1 vial of levofloxacin (100 ml of intravenous solution containing 500 mg of levofloxacin) should be at least 60 minutes.

Mixing with infusion solutions.

The drug is compatible with the following infusion solutions:

0.9% sodium chloride solution, 5% glucose monohydrate, 2.5% dextrose in Ringer's solution, multicomponent solutions for parenteral nutrition (amino acids, carbohydrates, electrolytes). The solution should be used within 3 hours after perforation of the vial. Treatment with levofloxacin after initial use of its intravenous form can be completed with the use of the oral form, provided that such treatment is acceptable for the individual patient.

Given the bioequivalence of parenteral and oral dosage forms, the same dose can be used. The duration of treatment depends on the course of the disease. As with other antibacterial agents, it is recommended to continue taking the drug for at least 48-72 hours after normalization of body temperature or confirmed microbiological destruction of pathogens. Dosage for adult patients with normal renal function, in whom creatinine clearance is more than 50 ml/min, is given in Table 3.

Table 3

1Duration of treatment includes intravenous and oral administration. The time to switch from intravenous to oral administration depends on the clinical picture, but usually lasts from 2 to 4 days.

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

Dosage for adult patients with renal impairment whose creatinine clearance is less than 50 mL/min is shown in Table 4.

Table 4

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

Dosage for patients with liver impairment.

No dose adjustment is required, as levofloxacin is metabolized to a minor extent in the liver and excreted mainly by the kidneys.

Dosage for elderly patients.

If renal function is not impaired, there is no need for dose adjustment.

Children.

The drug is contraindicated for use in children, as damage to the articular cartilage cannot be ruled out.

Overdose

Symptoms: dizziness, impaired consciousness/confusion, seizures, tremor, QT prolongation.

Treatment. In case of overdose, careful monitoring of the patient, including ECG, is necessary. Treatment is symptomatic. Hemodialysis, including peritoneal dialysis and NADPH, is not effective in removing levofloxacin from the body. There are no specific antidotes.

Adverse reactions

Adverse reactions are listed by system organ class and frequency: very common (≥1/10), common (≥1/100, <1/1000), uncommon (≥

On the part of the organs of vision*: rarely - visual disturbances, such as blurred vision; frequency unknown - temporary loss of vision, uveitis.

From the side of the organs of hearing and vestibular apparatus*: infrequently - vertigo; rarely - tinnitus; frequency unknown - hearing impairment, hearing loss.

Gastrointestinal: often - diarrhea, vomiting, nausea; infrequently - abdominal pain, dyspepsia, flatulence, constipation; frequency unknown - hemorrhagic diarrhea, which may indicate enterocolitis, including pseudomembranous colitis; pancreatitis. Liver and biliary tract: often - increased liver enzymes (ALT/AST, alkaline phosphatase, GGTP); infrequently - increased bilirubin in the blood; frequency unknown - jaundice and severe liver damage, including cases of acute liver failure, mainly in patients with severe underlying diseases, hepatitis.

Renal and urinary disorders: uncommon - increased serum creatinine; frequency unknown - acute renal failure (e.g. due to interstitial nephritis).

Metabolism and metabolism: infrequently - anorexia; rarely - hypoglycemia, especially in patients with diabetes; frequency unknown - hyperglycemia, hypoglycemic coma. Signs of hypoglycemia may include increased appetite, nervousness, increased sweating, tremor of the limbs.

On the part of the endocrine system: rarely - syndrome of inappropriate antidiuretic hormone secretion (SPAD).

Nervous system disorders: Common: headache, dizziness; uncommon: drowsiness, tremor, dysgeusia; rare: convulsions, paresthesias; frequency unknown: peripheral sensory or sensorimotor neuropathy, tactile sensory disturbances, parosmia, including anosmia, dyskinesia, extrapyramidal disorders, other motor coordination disorders, including gait, stuttering, ageusia, syncope, benign intracranial hypertension.

Psychiatric disorders*: often - insomnia; infrequently - anxiety, confusion, irritability, restlessness; rarely - psychotic disorders (including hallucinations, paranoia), depression, agitation, abnormal dreams, nightmares, fear; frequency unknown - psychotic disorders with self-destructive behavior, including suicidal thoughts or actions.

Cardiovascular system**: rarely - tachycardia, palpitations; frequency unknown - ventricular tachycardia, which can lead to cardiac arrest; ventricular arrhythmia and torsade de pointes type arrhythmia (mainly in patients with risk factors for QT prolongation), QT prolongation on ECG, arterial hypotension, collapse, vasculitis, phlebitis. Aneurysm, aortic dissection, regurgitation/insufficiency of any of the heart valves.

Blood and lymphatic system disorders: uncommon - leukopenia, eosinophilia; rare - neutropenia, thrombocytopenia, which causes an increased tendency to hemorrhages or bleeding; frequency unknown - pancytopenia, agranulocytosis, hemolytic anemia. Immune system disorders: rare - angioedema, hypersensitivity reactions, including anaphylactic shock, anaphylactoid shock (anaphylactic and anaphylactoid reactions can sometimes occur even after the first dose).

Skin and subcutaneous tissue disorders: uncommon - rash, pruritus, urticaria, skin redness, hyperhidrosis; rare - drug reaction with eosinophilia and systemic symptoms (DRESS), persistent drug erythema; frequency unknown - toxic epidermal necrolysis, Stevens-Johnson syndrome, exudative erythema multiforme, photosensitivity reactions, hypersensitivity to sunlight and ultraviolet radiation, leukocytic vasculitis, stomatitis. Musculoskeletal and connective tissue disorders*: uncommon - arthralgia, my