Levofloxacin-Darnitsa solution for infusion 500 mg bottle 100 ml No. 1

Instructions Levofloxacin-Darnitsa solution for infusion 500 mg bottle 100 ml No. 1

Composition

active ingredient: levofloxacin;

1 ml of solution contains levofloxacin hemihydrate equivalent to 5 mg levofloxacin;

Excipients: sodium chloride, diluted hydrochloric acid, sodium hydroxide, water for injections.

Dosage form

Solution for infusion.

Main physicochemical properties: clear yellow liquid with a greenish tint, practically free of particles.

Pharmacotherapeutic group

Antibacterials for systemic use. Antibacterials of the quinolone group. Fluoroquinolones. Levofloxacin. 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/DNA gyrase and topoisomerase IV complex. 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.

Limit values.

The European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommended minimum inhibitory concentration (MIC) breakpoints for levofloxacin that distinguish susceptible from moderately resistant and moderately resistant 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.

2 Low-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 Haemophilus influenzae.

3 Strains with MIC values above the breakpoint between susceptible and moderately resistant strains are very rare or have not yet been reported. Identification and antimicrobial susceptibility testing on any such isolates 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.

4 Oral and intravenous dose limits range from 500 mg once to 500 mg twice daily.

Antibacterial spectrum.

The prevalence of resistance for individual species may vary geographically and over time. It is desirable to obtain local information on resistance, especially when treating severe infections.

Usually sensitive species.

Aerobic Gram-positive bacteria: Bacillus anthracis, methicillin-sensitive Staphylococcus aureus, Staphylococcus saprophyticus, Streptococci - groups C and G, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes.

Aerobic gram-negative bacteria: Eikenella corrodens, Haemophilus influenzae, Haemophilus para-influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, 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 cloacae, Escherichia coli, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens.

Anaerobic bacteria: Bacteroides fragilis.

Naturally resistant strains.

Aerobic Gram-positive bacteria: Enterococcus faecium.

* Methicillin-resistant S.aureus may be resistant to fluoroquinolones, particularly levofloxacin.

Pharmacokinetics.

Absorption

Levofloxacin is rapidly and almost completely absorbed, Cmax is reached 1–2 hours after administration. Absolute bioavailability is approximately 99–100%. Food has little effect on the absorption of levofloxacin. Steady state is reached within 48 hours with a dosage regimen of 500 mg 1–2 times a day.

Distribution

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

Penetration into tissues and body fluids

Levofloxacin has been shown to penetrate bronchial mucosa, bronchial secretions of lung tissue, alveolar macrophages, lung tissue, skin (blister fluid), prostate tissue, and urine. However, levofloxacin penetrates poorly into cerebrospinal fluid.

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).

The mean apparent total clearance of levofloxacin after administration of 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 that these routes of administration are interchangeable.

Linearity

Levofloxacin has linear pharmacokinetics in the dose range of 50–1000 mg.

Patients with renal insufficiency

The pharmacokinetics of levofloxacin are affected by renal insufficiency. With decreased renal function, renal excretion and clearance are reduced, and half-lives are 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

The drug Levofloxacin-Darnitsa is prescribed to adults for the treatment of the following infectious diseases caused by microorganisms sensitive to levofloxacin:

community-acquired pneumonia*;

complicated skin and soft tissue infections*;

acute pyelonephritis and complicated urinary tract infections;

chronic bacterial prostatitis;

Pulmonary 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, other quinolones, or any component of the drug.

Adverse reactions from tendons after previous use of quinolones.

Epilepsy.

Children's age (up to 18 years).

Pregnancy or breastfeeding.

Interaction with other medicinal products and other types of interactions

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

A significant decrease in the seizure threshold is possible when quinolones are used simultaneously with theophylline, NSAIDs and other substances that lower the seizure threshold. The concentration of levofloxacin in the presence of fenbufen is approximately 13% higher than when levofloxacin is taken 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. This is because both drugs are able to block the tubular excretion of levofloxacin. Levofloxacin should be used with caution simultaneously with drugs that affect renal tubular secretion (probenecid and cimetidine), especially in patients with impaired renal function.

Cyclosporine.

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

Vitamin K antagonists.

When used simultaneously with vitamin K antagonists (e.g. warfarin), coagulation test values (prothrombin time/INR) 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 class IA and III antiarrhythmics, 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 information.

There is no clinically significant effect on the pharmacokinetics of levofloxacin when used together with the following drugs: calcium carbonate, digoxin, glibenclamide, ranitidine.

It is not recommended to drink alcohol while taking levofloxacin.

Application features

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

Patients with severe renal dysfunction, as well as severe cerebral atherosclerosis and cerebral circulation disorders should be careful when using the drug.

Throughout the course of treatment, it is necessary to monitor kidney and liver function.

When using the medicine, you should refrain from drinking alcohol.

In very severe pneumonia caused by pneumococci, levofloxacin may not provide optimal therapeutic effect.

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

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.

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 form of 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 treatment of anthrax.

Prolonged, disabling and potentially irreversible serious adverse reactions.

Very rare cases of prolonged (months or years) disabling and potentially irreversible serious adverse reactions affecting various body systems (musculoskeletal, nervous, mental and sensory) have been reported in patients treated with quinolones and fluoroquinolones, regardless of age or risk factors. Levofloxacin should be discontinued immediately at the first sign or symptom of any serious adverse reaction and patients should be advised to seek medical advice.

Duration of administration.

The recommended duration of administration is at least 60 minutes for 500 mg of the drug solution for infusion. With ofloxacin, tachycardia and a temporary increase in blood pressure are known to occur during infusion. In rare cases, a sharp decrease in blood pressure, circulatory collapse, is possible. If a pronounced decrease in blood pressure is observed during the administration of levofloxacin, the administration should be stopped immediately.

Aortic aneurysm and dissection and heart valve regurgitation/insufficiency.

Epidemiological studies suggest an increased risk of aortic aneurysm and dissection, particularly in the elderly, and of aortic and mitral valve regurgitation following the use of fluoroquinolones. Cases of aortic aneurysm and dissection, sometimes complicated by rupture (including fatal cases), and regurgitation/insufficiency of any of the cardiac valves have been reported in patients receiving fluoroquinolones (see section 4.8).

Therefore, fluoroquinolones should be used after careful benefit-risk assessment and after consideration of other treatment options in patients with a family history of aneurysm or congenital heart valve disease and in patients with a diagnosis of aortic aneurysm or dissection or with heart valve disease, or in the presence of other risk factors, such as:

Risk factors for both aortic aneurysm and dissection and heart valve regurgitation/insufficiency: connective tissue diseases such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behçet's disease, hypertension, rheumatoid arthritis;

Risk factors for developing aortic aneurysm and dissection: vascular disorders such as Takayasu arteritis or giant cell arteritis, atherosclerosis, Sjögren's syndrome;

Risk factors for the development of regurgitation/heart valve insufficiency: infective endocarditis.

The risk of aortic aneurysm and dissection and rupture is increased in patients receiving concomitant systemic corticosteroids.

In case of sudden abdominal, chest or back pain, patients should be advised to seek immediate medical attention in the emergency department.

Patients should be advised to seek immediate medical attention in the event of acute shortness of breath, new onset of palpitations, or development of abdominal or lower extremity edema.

In isolated cases, patients may experience tendinitis. Tendinitis and tendon rupture (including but not limited to the Achilles tendon), sometimes bilateral, may occur within the first 48 hours of starting treatment with quinolones or fluoroquinolones, and such cases have been reported even several months after stopping the drug. The risk of tendinitis and tendon rupture is increased in elderly patients, patients with impaired renal function, patients who have undergone solid organ transplantation, patients receiving a daily dose of 1000 mg of levofloxacin, and patients receiving concomitant corticosteroids. Therefore, concomitant use of corticosteroids should be avoided.

At the first signs of tendinitis (e.g. painful swelling, inflammation), levofloxacin should be discontinued immediately and alternative treatment options should be considered. Affected limbs should be treated appropriately (e.g. by immobilizing the tendon). Corticosteroids are not recommended if there are signs of tendinopathy.

Diseases caused by Clostridium difficile.

Diarrhea, particularly severe, persistent or bloody during or after treatment with levofloxacin, may be a symptom of Clostridium difficile-associated disease, the most severe form of which is pseudomembranous colitis. If pseudomembranous colitis is suspected, levofloxacin should be discontinued immediately and symptomatic and specific treatment (e.g. vancomycin) should be initiated without delay. Drugs that inhibit intestinal motility are contraindicated.

Patients with a tendency to seizures.

Quinolones may lower the seizure threshold and provoke the development of 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 lesions, during concomitant therapy with fenbufen and similar drugs or drugs that increase seizure readiness (lower the seizure threshold), such as theophylline (see section "Interaction with other medicinal products and other types of interactions"). If seizures occur, treatment with levofloxacin should be discontinued.

Patients with glucose-6-phosphate dehydrogenase deficiency.

In patients with latent or overt glucose-6-phosphate dehydrogenase deficiency, the use of quinolone antibacterial agents may lead to hemolytic reactions, therefore levofloxacin should be used with caution in such patients, monitoring the patient's condition for the possible occurrence of hemolysis.

Patients with renal failure.

Levofloxacin is excreted mainly by the kidneys, therefore dose adjustment is required for patients with renal insufficiency (see section "Method of administration and dosage").

Hypersensitivity reactions.

Levofloxacin may occasionally cause serious, potentially fatal hypersensitivity reactions (including 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 bullous reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis (also known as Lyell's syndrome), and drug rash with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported with levofloxacin. When prescribing the drug, patients should be warned about the signs and symptoms of severe skin reactions and monitored closely. If signs and symptoms suggestive of these reactions appear, levofloxacin should be discontinued immediately and alternative treatment should be considered. If a patient has a history of serious reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, or DRESS, levofloxacin should not be re-administered to this patient.

Change in blood glucose levels.

Changes in blood glucose levels (hyperglycemia and hypoglycemia) have been reported with the use of quinolones, especially in diabetic patients receiving concomitant oral hypoglycemic agents (including glibenclamide) or insulin. Cases of hypoglycemic coma have been observed. Patients with diabetes should monitor their blood sugar levels.

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, solariums) 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/international normalized ratio (INR)] and/or bleeding.

Psychotic reactions have been reported in patients receiving quinolones, including levofloxacin. Very rarely, these have resulted in suicidal ideation and self-harming behavior, sometimes even after a single dose of levofloxacin. If a patient develops 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 and women are more sensitive to drugs that prolong the QT interval. Therefore, fluoroquinolones, including levofloxacin, should be used with caution in these patients.

Peripheral neuropathy.

Cases of sensory or sensorimotor peripheral neuropathy resulting in paresthesia, hypoesthesia, dysesthesia, or weakness have been reported in patients receiving fluoroquinolones, including levofloxacin. Levofloxacin should be discontinued if a patient develops symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness to prevent the development of a potentially irreversible condition.

Exacerbation of myasthenia gravis.

Fluoroquinolones, including levofloxacin, block neuromuscular transmission and may cause 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 impairment.

If visual impairment 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 insensitive to the drug. If superinfection develops during therapy, appropriate measures should be taken.

Impact on laboratory tests.

In patients treated with levofloxacin, urine opiates may give false-positive results. It may be necessary to confirm positive results for opiates using more specific methods.

Levofloxacin may inhibit the growth of Mycobacterium tuberculosis, therefore a false-negative result is possible when performing bacteriological studies in patients with tuberculosis.

Hepatobiliary disorders.

Cases of necrotizing hepatitis, 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 seek medical advice if signs of liver disease such as anorexia, jaundice, dark urine, pruritus or abdominal pain occur.

Important information about excipients.

This medicinal product contains 860 mg sodium/dose. Caution should be exercised when used in 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

When using the drug, you should refrain from driving and potentially dangerous activities that require increased attention and speed of reaction, due to the possibility of developing adverse reactions from the nervous system (dizziness, numbness, drowsiness, confusion, vision and hearing disorders, motor disorders, including when walking).

Method of administration and doses

A sensitivity test must be performed before use.

The solution should be used within 3 hours after perforation of the vial.

The drug is administered intravenously 1–2 times a day.

The dose depends on the type and severity of the infection. The following dosage recommendations should be followed for patients with normal renal function (see Table 3) and creatinine clearance above 50 ml/min.

Table 3

1 Duration of treatment includes both intravenous and oral therapy. The time to switch from initial intravenous levofloxacin to oral administration at the same dosage depends on the patient's condition, but is usually possible 2-4 days after the start of treatment.

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

Dosage for patients with renal impairment (see Table 4) with creatinine clearance less than 50 mL/min.

Table 4

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

Dosage for patients with impaired liver function: No dose adjustment is required since levofloxacin is metabolized to a minor extent in the liver.

Dosage for elderly patients: If renal function is not impaired, no dose adjustment is necessary.

The drug should be administered slowly intravenously by drip infusion. The duration of administration should be at least 30 minutes for a dose of 250 mg or at least 60 minutes for a dose of 500 mg.

Depending on the patient's condition, after a few days it is possible to switch from intravenous administration to oral administration of levofloxacin with the same dosage.

The duration of treatment depends on the course of the disease. As with other antibacterial agents, it is recommended to continue treatment with levofloxacin for at least 48–72 hours after normalization of body temperature or confirmed eradication of pathogens by microbiological tests.

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).

Method of application

Do not insert the needle(s) into any areas of the polymer vial that are not intended for this purpose, but only into sterile ports!

To carry out infusion treatment, you must follow the following algorithm:

Remove the protective plastic cover with first-time opening control (if present).

Tear off the safety valve(s) No. 1 as shown in Fig. 1 and Fig. 2 (the manufacturer may use different types and materials for the safety valves).

Remove the cap from the needle and insert it into any of the special ports No. 2 of the infusion drug vial (see Fig. 1 and Fig. 2).

Another sterile port can be used to introduce other drugs into the infusion bottle (No. 4, see Fig. 3), or, in case of insufficient flow rate, for the air needle (No. 4, see Fig. 3).

Hang the solution bottle using the special ring No. 3 located at the bottom of the bottle (see Fig. 3).

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, hallucinations, tremor, prolongation of the QT interval or increased manifestations of other adverse reactions.

Treatment is symptomatic, according to clinical manifestations. In case of overdose, careful monitoring of the patient, including ECG, is necessary. Hemodialysis, including peritoneal dialysis or NAPD, is not effective in removing levofloxacin from the body. There are no specific antidotes.

Side effects

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 - < 1/10), uncommon (≥ 1/1,000 - < 1/100), rare (≥ 1/10,000 - < 1/1,000), very rare (< 1/10,000), frequency unknown (cannot be estimated from the available data).

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.

Hepatobiliary disorders: often - increased liver enzymes (alanine aminotransferase (ALT) / aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamyl transpeptidase (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: infrequently - increased serum creatinine; rarely - acute renal failure (e.g. due to interstitial nephritis).

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

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

Nervous system disorders: Common: headache, dizziness; uncommon: drowsiness, tremor, dysgeusia; rare: convulsions, paresthesias; frequency unknown: peripheral sensory or sensorimotor neuropathy, tactile disturbances, parosmia, including anosmia, dyskinesia, extrapyramidal disorders, other disorders of coordination of movements, particularly when walking, 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 (see section "Special warnings and precautions for use").

Cardiovascular system**: often - phlebitis; rarely - tachycardia, palpitations, hypotension; 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), prolongation of the QT interval on the electrocardiogram, collapse, vasculitis.

From the blood and lymphatic system: infrequently - leukopenia, eosinophilia; rarely - neutropenia, thrombocytopenia, which causes an increased tendency to hemorrhages or bleeding; frequency unknown - pancytopenia, agranulocytosis, hemolytic anemia.

Immune system disorders: Rare: hypersensitivity reactions, angioedema; Frequency unknown: anaphylactic shock, anaphylactoid shock. Anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose.

Skin and subcutaneous tissue disorders: uncommon - rash, itching, urticaria, hyperhidrosis; rare - drug rash with eosinophilia and systemic symptoms (DRESS syndrome), local drug rash; frequency unknown - toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, exudative erythema multiforme, hypersensitivity to sunlight and ultraviolet radiation (photosensitivity reactions), leukocytic vasculitis, stomatitis. Sometimes, mucocutaneous reactions may occur even after the first dose.

Infections and infestations: uncommon - fungal infections, including Candida species, overgrowth of other resistant microorganisms.

From the side of the musculoskeletal system and connective tissue