Floxium film-coated tablets 500 mg blister No. 10

Instructions Floxium film-coated tablets 500 mg blister No. 10

Composition

active ingredient: levofloxacin;

1 tablet contains levofloxacin hemihydrate equivalent to levofloxacin – 500 mg;

excipients: crospovidone (polyplasdone XL), microcrystalline cellulose, potato starch, talc, hypromellose (hydroxypropylmethylcellulose), sodium lauryl sulfate, sodium starch glycolate (type A), calcium stearate, coating mixture "Opadry II Yellow" 33G22507 (contains: triacetin; hypromellose; lactose, monohydrate; titanium dioxide (E 171); polyethylene glycol; iron oxide yellow (E 172)).

Dosage form

Film-coated tablets.

Main physicochemical properties: film-coated tablets of creamy yellow color, oval shape with a biconvex surface, with a score on one side of the tablet and embossing "KMP" on the other side. A yellowish core is visible on the cross section.

Pharmacotherapeutic group

Antibacterial agents of the quinolone group. Fluoroquinolones.

ATX code J01M A12.

Pharmacological properties

Pharmacodynamics.

Levofloxacin is characterized by a broad spectrum of antibacterial activity. The bactericidal effect is provided by the inhibition by levofloxacin of the bacterial enzyme DNA gyrase, which belongs to type II topoisomerases. The result of such inhibition is the inability of bacterial DNA to transition from a relaxed state to a supercoiled state, which, in turn, makes further division (reproduction) of bacterial cells impossible. The spectrum of activity of the drug Floxium® includes gram-positive, gram-negative bacteria, along with non-fermenting bacteria.

Typically sensitive species

Gram-positive aerobes: Bacillus anthracis, Staphylococcus aureus methicillin-sensitive, Staphylococcus saprophyticus Streptococci, group C and G, Streptococcus agalactiae, Streptococcus pneumonia, Streptococcus pyogenes.

Gram-negative aerobes: Eikenella corrodens, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella oxytoca, Moraxella catarrhalis, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri.

Anaerobes: Peptostreptococcus.

Others: Chlamydophila pneumonia, Chlamydophila psittaci, Chlamydia trachomatis, Legionella pneumophila, Mycoplasma pneumonia, Mycoplasma hominis, Ureaplasma urealyticum.

Species with possible acquired resistance

Gram-positive aerobes: Enterococcus faecalis, methicillin-sensitive Staphylococcus aureus, coagulase-negative Staphylococcus spp.

Gram-negative aerobes: Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens.

Anaerobes: Bacteroides fragilis.

Naturally resistant strains

Gram-positive aerobes: Enterococcus faecium.

Mechanism of resistance development

Resistance to levofloxacin develops as a stepwise mutation of the target site in both types of topoisomerase II, DNA gyrase and topoisomerase IV. Other mechanisms of resistance, such as permeability (characteristic of Pseudomonas aeruginosa) and efflux mechanisms, may also influence susceptibility to levofloxacin.

Cross-resistance between levofloxacin and other fluoroquinolones has been observed. Given the mechanism of action, there is no cross-resistance between levofloxacin and other classes of antibacterial agents.

Breakpoint concentrations of the antibiotic (or the limit values of the diameter of the zone of inhibition of the growth of the microorganism).

EUCAST (European Committee on Antimicrobial Susceptibility Testing) recommends the minimum inhibitory concentration (MIC) of levofloxacin for determining susceptibility from intermediately susceptible organisms and intermediately resistant microorganisms, presented in Table 1 according to MIC test data (mg/L).

Table 1

Clinically determined EUCAST MICs for levofloxacin (version 2.0, 2012-01-01)

The prevalence of resistance may vary geographically and over time for individual species, so local information on resistance is important, particularly in the treatment of severe infections. Expert advice should be sought when the local prevalence of resistance is such that the usefulness of the agent, at least for some types of infection, is questionable.

Pharmacokinetics.

Absorption. Levofloxacin is rapidly and almost completely absorbed after oral administration, with peak plasma concentrations occurring 1–2 hours after dosing. Absolute bioavailability is 99–100%. Absorption is slightly affected by food intake. Steady-state values are reached within 48 hours after administration of 500 mg 1–2 times 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 doses of 500 mg, indicating good distribution into body tissues.

The cumulative effect of levofloxacin at a dosage of 500 mg once a day is not clinically significant and can be neglected. There is a slight but predictable accumulation at a dosage of 500 mg twice a day. Steady-state distribution is achieved within 3 days.

Distribution in bronchial mucosa and bronchial epithelial secretions. The maximum concentration of levofloxacin in bronchial mucosa and bronchial epithelial secretions at a dose above 500 mg per os is 8.3 and 10.8 μg/ml, respectively.

Distribution in lung tissue. The maximum concentration of levofloxacin in lung tissue at a dose of more than 500 mg per os is approximately 11.3 μg/ml and is reached within 4-6 hours after administration. The concentration in the lungs exceeds that in blood plasma.

Distribution in blister fluid: The maximum concentration of levofloxacin in blister fluid after administration of 500 mg 1 and 2 times a day is 4.0 and 6.7 μg/ml, respectively.

Distribution in cerebrospinal fluid: Levofloxacin penetrates poorly into the cerebrospinal fluid.

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

Urine concentration: The mean concentration of levofloxacin within 8-12 hours after a single dose of 150 mg, 300 mg or 500 mg per os is 44 μg/ml, 91 μg/ml, 200 μg/ml, respectively.

Metabolism: Levofloxacin is metabolized to a minor extent, its metabolites are desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for less than 5% of the amount of drug excreted in the urine.

Elimination: After oral administration, levofloxacin is eliminated from plasma very slowly (half-life 6-8 hours). Excretion is mainly renal (more than 85% of the administered dose). There is no significant difference in the pharmacokinetics of levofloxacin after intravenous and oral administration.

Levofloxacin is subject to linear pharmacokinetics in the range of 50 to 600 mg.

Indication

Floxium® is indicated for the treatment of infections caused by levofloxacin-sensitive microorganisms in adults:

acute bacterial sinusitis;

exacerbation of chronic obstructive pulmonary disease, including bronchitis;

community-acquired pneumonia;

uncomplicated cystitis;

complicated skin and soft tissue infections.

In the treatment of the above infections, the drug is used only when the use of other antibacterial agents, which are usually prescribed for the initial treatment of these infections, is not possible;

complicated urinary tract infections (including acute pyelonephritis);

chronic bacterial prostatitis;

Pulmonary anthrax: post-exposure prophylaxis and treatment.

Floxium® in this dosage form (tablets) can be used to complete the course of therapy in patients who have demonstrated improvement during the initial treatment with Floxium®, solution for infusion.

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

Contraindication

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

Epilepsy.

Tendon damage associated with previous use of fluoroquinolones.

Childhood.

Pregnancy and breastfeeding.

Interaction with other medicinal products and other types of interactions

Effects of other medicinal products on levofloxacin

Iron salts, zinc salts, antacids containing magnesium and aluminum, didanosine.

The absorption of levofloxacin is significantly reduced when taken simultaneously with iron salts and antacids containing magnesium or aluminum, or didanosine (only for forms containing aluminum or magnesium buffering agents). The simultaneous use of fluoroquinolones with multivitamins containing zinc leads to a decrease in their absorption when taken orally.

The tablets should be taken at least 2 hours after taking drugs containing divalent or trivalent cations, such as iron salts or antacids containing magnesium or aluminum. Calcium carbonate had a minimal effect on the absorption of levofloxacin when administered orally.

The bioavailability of levofloxacin is significantly reduced when the drug is used simultaneously with sucralfate. If the patient needs to receive both sucralfate and levofloxacin, it is better to take sucralfate 2 hours after taking Floxium® tablets.

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

No pharmacokinetic interaction of levofloxacin with theophylline has been identified. However, a significant decrease in the seizure threshold may occur with the simultaneous use of quinolones with theophylline, NSAIDs and other agents that lower the seizure threshold.

Levofloxacin concentrations in the presence of fenbufen were approximately 13% higher than when levofloxacin was administered alone.

Probenecid and cimetidine

Probenecid and cimetidine have a statistically significant effect on the elimination of levofloxacin.

Renal clearance of levofloxacin is reduced by 24% in the presence of cimetidine and by 34% in probenecid. This is because both drugs are able to block the tubular secretion of levofloxacin. However, in the study, statistically significant kinetic differences were not clinically relevant.

Levofloxacin should be administered with caution simultaneously with drugs that affect tubular secretion, such as probenecid and cimetidine, especially in patients with renal insufficiency.

Other drugs

It is known that no clinically significant effect was caused on the pharmacokinetics of levofloxacin when levofloxacin was used together with calcium carbonate, digoxin, glibenclamide, ranitidine.

Effect of levofloxacin on other drugs

Cyclosporine

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

Vitamin K antagonists

Coagulation monitoring is recommended in patients receiving concomitant vitamin K antagonists (e.g. warfarin) due to increased international normalized ratio (INR) and/or bleeding, which may be severe.

QT-prolonging drugs

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 4.4.

Other significant information

There was no effect of levofloxacin on the pharmacokinetics of theophylline (which is a marker substrate for the CYP1A2 enzyme), indicating that levofloxacin is not a CYP1A2 inhibitor.

Eating

No clinically significant interaction with food has been observed. Thus, Floxium® tablets can be taken regardless of food intake.

Application features

Levofloxacin should be avoided in patients who have had a history of serious adverse reactions to quinolones or fluoroquinolones. Treatment of these patients should only be initiated when 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, patients treated with quinolones and fluoroquinolones, regardless of age or risk factors, have experienced prolonged (months or years), disabling and potentially irreversible serious adverse reactions affecting various body systems (including musculoskeletal, nervous, mental and sensory). If signs or symptoms of any serious adverse reaction occur, the drug should be discontinued immediately and a doctor should be consulted.

Aortic aneurysm and dissection and heart valve regurgitation/insufficiency

Epidemiological studies have reported an increased risk of aortic aneurysm and dissection, especially in the elderly, 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 cases of regurgitation/insufficiency of any of the heart valves have been reported in patients treated with 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, such as:

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

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

§ risk factors for regurgitation/heart valve insufficiency: infective endocarditis.

Patients should seek immediate medical attention if they experience sudden abdominal, chest, or back pain. Patients should be advised to seek immediate medical attention if they experience severe shortness of breath, new onset palpitations, or develop abdominal or lower extremity swelling.

Methicillin-resistant S. aureus

Methicillin-resistant S. aureus (MRSA) has a very high probability of being co-resistant to fluoroquinolones, including levofloxacin. Therefore, levofloxacin is not recommended for the treatment of infections known or suspected to be caused by MRSA, unless laboratory tests have confirmed that the pathogen is susceptible to levofloxacin.

Levofloxacin can be used to treat acute bacterial sinusitis and exacerbation of chronic bronchitis, if these infections have been appropriately diagnosed.

Fluoroquinolone resistance in E. coli (a common cause of urinary tract infections) varies between countries. The local prevalence of fluoroquinolone resistance in E. coli should be taken into account when prescribing fluoroquinolones.

In the case of pulmonary anthrax, the use of the drug is based on in vitro susceptibility data of Bacillus anthracis and experimental animal data, as well as limited data on human use. Physicians should consider national and/or international consensus documents on the treatment of anthrax.

Tendinitis and tendon rupture.

Tendinitis, which may lead to tendon rupture, including Achilles tendon, has been reported rarely with quinolones. Tendinitis and tendon rupture, sometimes bilateral, may occur within 48 hours of starting treatment with quinolones and fluoroquinolones. Tendinitis and tendon rupture have been reported even up to several months after discontinuation of treatment in patients receiving daily doses of 1000 mg levofloxacin. The risk of tendinitis and tendon rupture is increased in the elderly, in patients with renal impairment, in patients with organ transplants and in patients receiving concomitant corticosteroids. Therefore, concomitant use of corticosteroids should be avoided.

At the first sign of tendinitis (e.g. painful swelling, inflammation), treatment with the drug should be discontinued and alternative treatment should be considered. The affected limb should be treated appropriately (e.g. by immobilizing the tendon) (see sections 4.3 and 4.8). Corticosteroids should not be used if signs of tendinopathy develop.

Myoclonus

Myoclonus has been reported in patients receiving levofloxacin (see section 4.8). The risk of myoclonus is increased in the elderly and in patients with renal insufficiency unless the levofloxacin dose is adjusted according to creatinine clearance. Levofloxacin should be discontinued immediately at the first appearance of myoclonus and appropriate treatment initiated.

Blood disorders

Bone marrow failure, including leukopenia, neutropenia, pancytopenia, haemolytic anaemia, thrombocytopenia, aplastic anaemia or agranulocytosis, may occur during treatment with levofloxacin (see section 4.8). If any of these disorders are suspected, blood tests should be monitored. If abnormal results are obtained, discontinuation of levofloxacin should be considered.

Diseases caused by Clostridium difficile

Diarrhea, particularly severe, persistent and/or hemorrhagic, during or after treatment (up to several weeks after the end of treatment) with the drug may be a symptom of Clostridium difficile-associated disease, the most severe form of which is pseudomembranous colitis. If pseudomembranous colitis is suspected, the drug should be discontinued immediately and supportive therapy and, if necessary, specific therapy (e.g., oral vancomycin) should be initiated as soon as possible.

Agents that inhibit intestinal motility are contraindicated in this clinical situation.

Patients prone to seizures

Levofloxacin is contraindicated in patients with a history of epilepsy. As with other quinolones, Floxium® should be used with extreme caution in patients prone to seizures, such as those with central nervous system lesions, during concomitant therapy with fenbufen and similar NSAIDs 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

Patients with latent or present defects in glucose-6-phosphate dehydrogenase activity may be prone to hemolytic reactions when treated with quinolone antibacterial agents, therefore levofloxacin should be used with caution and monitored for possible hemolysis.

Patients with renal insufficiency

Since levofloxacin is excreted mainly by the kidneys, dose adjustment is required for patients with impaired renal function (renal failure), see section "Method of administration and dosage".

Levofloxacin may occasionally cause serious, potentially fatal hypersensitivity reactions (e.g. angioedema up to and including anaphylactic shock) after the initial dose of the drug (see section 4.8). In such cases, patients should discontinue treatment immediately and consult a doctor.

Severe skin reactions.

Severe skin 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 can be fatal, have been reported with levofloxacin. Patients should be advised of the signs and symptoms of severe skin reactions before initiating treatment and monitored closely. If signs and symptoms suggestive of these reactions occur, levofloxacin should be discontinued immediately and alternative treatment considered. If a patient has experienced reactions such as TSN, TEN, or DRESS while receiving levofloxacin, levofloxacin should not be re-administered to that patient under any circumstances.

Change in blood glucose levels

Changes in blood glucose levels (both 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 reported. Blood sugar levels should be monitored in diabetic patients.

Prevention of photosensitivity

Photosensitivity has been reported with levofloxacin. To avoid this, patients are advised not to expose themselves to strong sunlight or artificial UV radiation (e.g. artificial UV lamps, solariums) while taking levofloxacin and for 48 hours after stopping the drug.

Patients receiving vitamin K antagonists

Due to the possible increase in coagulation tests (prothrombin time/MTX) and/or bleeding in patients receiving levofloxacin in combination with a vitamin K antagonist (e.g. warfarin), coagulation tests should be monitored if these medicinal products are used concomitantly (see section 4.5).

Psychotic reactions

Psychotic reactions have been reported in patients taking quinolones, including levofloxacin.

In very rare cases, they have progressed to suicidal ideation and self-harm, sometimes after only a single dose of levofloxacin (see section 4.8). If a patient experiences these reactions, levofloxacin should be discontinued and appropriate measures taken.

It is recommended that levofloxacin be used with caution in patients with psychotic disorders or patients with a history of mental illness.

QT prolongation

Floxium® should be used with caution in patients with known risk factors for QT prolongation, such as:

congenital long QT syndrome;

concomitant use of drugs 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 younger women may be more sensitive to drugs that prolong the QT interval, therefore caution should be exercised when administering levofloxacin to these categories of patients (see sections “Interaction with other medicinal products and other types of interactions”, “Method of administration and dosage”; “Elderly patients”; “Overdose”, “Adverse reactions”).

Peripheral neuropathy.

Sensory or sensorimotor peripheral neuropathy resulting in paresthesia, hypoesthesia, dysesthesia, or weakness has been reported in patients receiving fluoroquinolones, including levofloxacin. If a patient experiences symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness, levofloxacin should be discontinued and a physician consulted to prevent the development of an irreversible condition.

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 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 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, and levofloxacin is not recommended for use in patients with a history of myasthenia gravis.

There are reports (22 reports worldwide) of the development of retinal detachment with the use of fluoroquinolone antibiotics.

If visual impairment or other effects on the eyes are observed, an ophthalmologist should be consulted immediately (see sections “Ability to influence the reaction speed when driving vehicles or using other mechanisms”, “Adverse reactions”).

Superinfection

When using levofloxacin, especially long-term, the growth of resistant microorganisms is possible. 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 opiates with more specific methods.

Levofloxacin inhibits the growth of Mycobacterium tuberculosis, therefore a false-negative result is possible when conducting a bacteriological study in patients with tuberculosis.

Excipients (lactose)

The drug contains lactose, so it should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding

Pregnancy: There are limited data from the use of levofloxacin in pregnant women.

Due to the lack of human studies and the possible damage of quinolones to articular cartilage in a growing body, Floxium® is contraindicated for pregnant and breastfeeding women.

If pregnancy is established during treatment with Floxium®, the doctor should be informed.

Breastfeeding period. Floxium® is contraindicated for use during breastfeeding.

There is insufficient information on the excretion of levofloxacin into breast milk, although other fluoroquinolones are excreted in breast milk. Due to the lack of human studies and the possible damage of fluoroquinolones to articular cartilage in the growing body, Floxium® should not be administered to women who are breastfeeding.

Fertility.

Levofloxacin did not cause impairment of fertility and reproductive function in rats.

Ability to influence reaction speed when driving vehicles or other mechanisms

Patients who drive vehicles, work with machines and mechanisms should take into account possible adverse reactions from the nervous system (dizziness/vertigo, numbness, drowsiness, confusion, visual and hearing disorders, movement disorders).

Method of administration and doses

Floxium® tablets are taken 1–2 times a day. The dose depends on the type, severity of the infection and the sensitivity of the probable pathogen.

Floxium® in this dosage form (tablets) can be used to complete the course of therapy in patients who have demonstrated improvement during the initial treatment with Floxium®, solution for infusion, using the same doses.

The duration of treatment depends on the course of the disease and is no more than 14 days. It is recommended to continue using the drug for at least 48–72 hours after normalization of body temperature or confirmed destruction of pathogens by microbiological tests.

Floxium® tablets should be swallowed without chewing, with sufficient liquid. For ease of dosing, the tablet can be divided along the score line. The tablets can be taken regardless of food intake.

The drug should be administered at least 2 hours before or after the use of iron salts, zinc salts, antacids containing magnesium or aluminum, didanosine (only for forms containing aluminum or magnesium in buffering agents) and sucralfate (see section "Interaction with other medicinal products and other types of interaction").

Table 2

Recommended dosage for adult patients with normal renal function, with creatinine clearance above 50 ml/min

Special populations

Table 3

Dosage for patients with renal impairment with creatinine clearance less than 50 mL/min

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

Dosage for patients with hepatic impairment: No dosage adjustment is required since levofloxacin is only slightly metabolized in the liver and is excreted primarily by the kidneys.

Dosage for elderly patients: If renal function is not impaired, no dose adjustment is required (see section "Special warnings and precautions for use").

Children. Floxium® is contraindicated for use in children and adolescents due to the risk of damage to articular cartilage.

Overdose

Symptoms of levofloxacin overdose include central nervous system disorders (confusion, dizziness, impaired consciousness and convulsions, myoclonus); gastrointestinal reactions such as nausea and erosion of the mucous membranes; possible prolongation of the QT interval. Hallucinations and tremor are possible.

Treatment: symptomatic. ECG monitoring should be considered, as QT prolongation may occur. Antacids are used to protect the gastric mucosa. Hemodialysis, including peritoneal dialysis or chronic ambulatory peritoneal dialysis (CHAP), is not effective in removing levofloxacin from the body. There are no specific antidotes.

Side effects

The frequency of side effects was determined using the following criteria: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (≥1/10,000), frequency unknown (cannot be estimated from the available data).

Infections and infestations:

uncommon: fungal infections, including Candida species, proliferation of other resistant microorganisms.

From the blood and lymphatic system:

infrequently: leukopenia, eosinophilia;

rarely: thrombocytopenia, neutropenia;

frequency unknown: bone marrow failure, including aplastic anemia, agranulocytosis, pancytopenia, hemolytic anemia.

On the part of the immune system:

Rare: angioedema, hypersensitivity;

frequency unknown: anaphylactic shock, anaphylactoid shock

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

Metabolism and nutrition:

uncommon: anorexia;

Rare: hypoglycemia, especially in patients with diabetes;

frequency unknown: hyperglycemia, hypoglycemic coma.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH, rare)

From the psyche:

common: insomnia;

Uncommon: nervousness, confusion, anxiety.

Rare: psychotic disorders (including hallucinations, paranoia), depression, agitation, unusual dreams, nightmares;

frequency unknown: mania, psychotic reactions with self-destructive behavior, including suicidal thoughts or actions

Nervous system*:

common: headache, dizziness;

frequency unknown: drowsiness, tremor, dysgeusia (subjective taste disturbance);

rare: conv