Polymic film-coated tablets No. 10

Instructions for Polimik film-coated tablets No. 10

Composition

active ingredients: 1 tablet contains ofloxacin 200 mg and ornidazole 500 mg;

Excipients: microcrystalline cellulose, sodium starch glycolate (type A), povidone
(K-30), magnesium stearate, Opadry 03B53217 orange coating: hypromellose, titanium dioxide (E 171), sunset yellow FCF (E 110), polyethylene glycols.

Dosage form

Film-coated tablets.

Main physicochemical properties: capsule-shaped, film-coated tablets, orange in color, with a break line on one side.

Pharmacotherapeutic group

Combined antibacterial agents. ATX code J01R A.

Pharmacological properties

Pharmacodynamics.

Polymic® is a combined antimicrobial and antiprotozoal drug, the pharmacological action of which is due to the properties of its components: ofloxacin (a quinolinecarboxylic acid derivative) and ornidazole (a 5-nitroimidazole derivative).

Mechanism of action of ofloxacin.

Ofloxacin has a broad spectrum of antibacterial activity against both Gram-negative and Gram-positive microorganisms.

The main mechanism of action of ofloxacin is the specific inhibition of DNA gyrase, an enzyme necessary for replication, transcription, repair and recombination of bacterial DNA. Inhibition of this enzyme leads to expansion and destabilization of the DNA of the bacterial cell, and therefore to its death. It has been established that some quinolones, including ofloxacin, have another, non-RNA-dependent effect on bacterial cells, which enhances the bactericidal effect. The nature of this effect is not fully understood.

Pharmacokinetics/pharmacodynamics relationship.

Fluoroquinolones have concentration-dependent bactericidal activity and exhibit a moderate post-antibiotic effect. For this class of antimicrobial drugs, the relationship between the area under the concentration-time curve (AUC) and the minimum inhibitory concentration (MIC) or maximum concentration (Cmax) and the MIK predicts clinical success.

Mechanism of resistance.

Resistance to ofloxacin is acquired by a stepwise process of target site mutation in both types of topoisomerase II, DNA gyrase, and topoisomerase IV. Other resistance mechanisms, such as barrier penetration (common in Pseudomonas aeruginosa) and efflux mechanisms, may also influence susceptibility to ofloxacin.

Antibacterial spectrum.

Therapeutic doses of ofloxacin have no pharmacological effect on the somatic or autonomic nervous system.

Mechanism of action of ornidazole.

Ornidazole is active against Trichomonas vaginalis, Entamoeba histolytica, Giardiasis lamliasis (Giardia intestinalis), as well as some anaerobic bacteria such as Bacteroides, Clostridium spp., Fusobacterium spp., and anaerobic cocci.

By the mechanism of action, ornidazole is a DNA-tropic drug with selective activity against microorganisms that have enzyme systems capable of reducing the nitro group and catalyzing the interaction of ferridoxine group proteins with nitro compounds. After ornidazole penetrates the microbial cell, its mechanism of action is due to the reduction of the nitro group under the influence of nitroreductases of the microorganism and the activity of the already reduced nitroimidazole. The reduction products form complexes with DNA, causing its degradation, disrupting the processes of DNA replication and transcription. In addition, the products of ornidazole metabolism have cytotoxic properties and disrupt the processes of cellular respiration of microorganisms.

Pharmacokinetics.

Not studied.

Indication

Treatment of mixed infections caused by pathogens (microorganisms and protozoa) sensitive to the components of the medicinal product:

– diseases of the genitourinary system: acute pyelonephritis, bacterial prostatitis, uncomplicated cystitis, epididymitis, complicated urinary tract infections.

– sexually transmitted diseases.

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

Contraindication

Hypersensitivity to ofloxacin, ornidazole, other fluoroquinolone derivatives, nitroimidazole derivatives or other components of the drug;

history of tendinitis or tendon rupture associated with the use of fluoroquinolones;

epilepsy, including a history;

lowered seizure threshold;

central nervous system damage (including multiple sclerosis);

childhood (up to 18 years old);

pregnancy;

breastfeeding period;

glucose-6-phosphate dehydrogenase deficiency;

blood dyscrasia or other hematological disorders;

QT interval prolongation;

uncompensated hypoglycemia;

simultaneous use of class IA (zinidine, procainamide) or class III (amiodarone, sotalol) antiarrhythmics, tricyclic antidepressants, macrolides.

Polymic® should be avoided in patients with a history of serious adverse reactions to quinolone or fluoroquinolone-containing medicinal products (see section 4.8). Treatment of such patients with Polymic® should only be initiated when no alternative treatment options are available and after a careful benefit-risk assessment (see section 4.4).

Interaction with other medicinal products and other types of interactions

Interactions associated with ofloxacin.

Antihypertensive drugs

When ofloxacin is used simultaneously with antihypertensive agents or during barbiturate anesthesia, a sudden decrease in blood pressure is possible. In such cases, cardiovascular function should be monitored.

Drugs that prolong the QT interval.

It is contraindicated to use ofloxacin simultaneously with drugs that prolong the QT interval [(class IA (quinine, procainamide) and class III (amiodarone, sotalol) antiarrhythmics, tricyclic antidepressants, macrolides)].

Ofloxacin, like other fluoroquinolones, should be used with caution in patients receiving antipsychotics.

Nonsteroidal anti-inflammatory drugs (NSAIDs), nitroimidazole derivatives and methylxanthines.

The simultaneous use of ofloxacin with NSAIDs (including phenylpropionic acid derivatives), nitroimidazole derivatives and methylxanthines increases the risk of nephrotoxic effects and enhances the stimulating effect on the central nervous system, which leads to a decrease in the seizure threshold. In the event of seizures, the drug should be discontinued.

Theophylline.

No pharmacokinetic interaction of ofloxacin with theophylline was found.

Theophylline steady-state serum concentrations, half-life, and risk of theophylline-related adverse reactions may be increased with concomitant use. Serum theophylline levels should be monitored closely and theophylline dosage adjusted as necessary. Adverse reactions (including seizures) may occur with or without increased serum theophylline levels.

Drugs that lower the threshold of seizure activity.

If quinolones are used simultaneously with other drugs that lower the seizure threshold, such as theophylline, an additional decrease in the seizure threshold of the brain may be observed.

Drugs secreted by tubular secretion.

Concomitant use of high doses of ofloxacin with drugs excreted by tubular secretion may lead to increased plasma concentrations due to decreased excretion.

Drugs metabolized by cytochrome P450.

Since the simultaneous use of most quinolones, including ofloxacin, inhibits the enzymatic activity of cytochrome P450, the simultaneous use of ofloxacin with drugs metabolized by this system (cyclosporine, theophylline, methylxanthine, caffeine, warfarin) prolongs the half-life of these drugs.

Anticoagulants, including vitamin K antagonists.

Prolonged bleeding time has been reported with the concomitant use of ofloxacin and anticoagulants.

When ofloxacin is used concomitantly with vitamin K antagonists (e.g. warfarin), increases in coagulation tests [(prothrombin time (PT)/international normalized ratio (INR)] and/or bleeding, which may be severe, have been reported. Therefore, coagulation parameters should be monitored in patients receiving concomitant vitamin K antagonists due to a possible increase in the activity of coumarin derivatives (see section 4.4).

Drugs that reduce the absorption of ofloxacin.

Simultaneous use of the drug Polimik® with antacids containing calcium, magnesium or aluminum, with sucralfate, with bivalent or trivalent iron, with multivitamins containing zinc, reduces the absorption of ofloxacin. Therefore, the interval between the use of these drugs should be at least 4 hours.

When ofloxacin is used concomitantly with oral hypoglycemic drugs and insulin, hypoglycemia or hyperglycemia is possible, therefore, it is necessary to monitor parameters for their compensation. When used concomitantly, ofloxacin may cause a slight increase in serum concentrations of glibenclamide; patients receiving this combination should be carefully monitored.

Probenecid, cimetidine, furosemide and methotrexate.

Simultaneous use of ofloxacin with probenecid, cimetidine, furosemide, methotrexate leads to an increase in the concentration of ofloxacin in the blood plasma and an increase in the risk of its toxic effects.

Drugs that increase urine pH.

When used with urine alkalizing agents (carbonic anhydrase inhibitors, citrates, sodium bicarbonate), the risk of crystalluria and nephrotic effects increases.

Laboratory studies.

During treatment with ofloxacin, false-positive results may be observed in the determination of opiates or porphyrins in urine. Therefore, more specific methods should be used.

Ofloxacin may inhibit the growth of Mycobacterium tuberculosis and give false-negative results in bacteriological tests for the diagnosis of tuberculosis.

Interactions associated with ornidazole.

Alcohol.

Although ornidazole (unlike other nitroimidazole derivatives) does not inhibit aldehyde dehydrogenase, alcohol should not be consumed during therapy with Polymic® and for at least 3 days after its discontinuation.

Anticoagulants.

Ornidazole enhances the effect of oral coumarin anticoagulants, which increases the risk of bleeding, so their dosage should be adjusted accordingly.

Veruconia bromide.

Ornidazole prolongs the muscle relaxant effect of vecuronium bromide.

Liver enzyme inducers.

Concomitant use of phenobarbital or other enzyme inducers with ornidazole reduces its circulation period in the blood serum.

Liver enzyme inhibitors.

Concomitant use of enzyme inhibitors (e.g. cimetidine) with ornidazole increases its circulation period in the blood serum.

Lithium.

The concomitant use of ornidazole with drugs containing lithium salts should be accompanied by monitoring of lithium and electrolyte concentrations, as well as serum creatinine levels (see section "Special warnings and precautions for use").

Application features

Before starting treatment, it is necessary to perform tests: culture for microflora and determination of sensitivity to ofloxacin and ornidazole.

In case of side effects, especially from the nervous system, allergic reactions, severe arterial hypotension, which may occur immediately after the first dose, the drug Polimik® must be discontinued.

When using high doses of the drug Polymic® and in case of continuation of therapy for more than 10 days, clinical and laboratory monitoring is recommended.

The effect of other medicines may be enhanced or weakened during treatment with the drug.

Features of use associated with ofloxacin.

Polymic® should be avoided in patients with a history of serious adverse reactions to quinolones or fluoroquinolones (see section "Adverse reactions"). Treatment of such patients with Polymic® should only be initiated when there are no alternative treatment options and after a careful benefit-risk assessment (see also section "Contraindications").

Prolonged, disabling and potentially irreversible serious adverse reactions.

Very rare, prolonged (months or years), disabling and potentially irreversible serious adverse reactions affecting various organ systems (musculoskeletal, nervous, mental and sensory) have been reported in patients treated with quinolones and fluoroquinolones, regardless of age or risk factors. At the first signs or symptoms of any serious adverse reaction, the use of Polimik® should be discontinued immediately and a doctor should be consulted.

Peripheral neuropathy.

Cases of sensory or sensorimotor polyneuropathy resulting in paresthesia, hypoesthesia, dysesthesia or weakness have been reported in patients receiving quinolones or fluoroquinolones. Patients taking Polymic® are advised to inform their doctor of the development of symptoms of neuropathy such as pain, burning, tingling, numbness or weakness before continuing treatment to prevent the development of a potentially irreversible condition (see section "Adverse Reactions"). If peripheral neuropathy occurs, treatment should be discontinued.

Patients with a tendency to seizures.

Quinolones may lower the seizure threshold and cause seizures. Polimik® is contraindicated in patients with epilepsy, including a history of epilepsy, or a lowered seizure threshold (see section "Contraindications").

The simultaneous use of ofloxacin with NSAIDs (including phenylpropionic acid derivatives), nitroimidazole derivatives and methylxanthines enhances the stimulating effect on the central nervous system, which leads to a decrease in the seizure threshold (see section "Interaction with other medicinal products and other types of interactions").

If seizures occur, the drug should be discontinued.

Fluoroquinolones, including ofloxacin, 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 associated with the use of fluoroquinolones in patients with myasthenia gravis during post-marketing experience. Polimik® is not recommended for use in patients with a history of myasthenia gravis.

Patients with a history of psychotic disorders.

Psychotic reactions have been reported in patients taking fluoroquinolones. In very rare cases, these have progressed to suicidal thoughts and self-harming behavior, including suicide attempts, sometimes after only a single dose of ofloxacin (see section 4.8). If a patient experiences these reactions, Polimik® should be discontinued and appropriate measures should be taken. Caution is advised in patients with psychotic disorders or a history of psychiatric illness.

Hypersensitivity reactions and allergic reactions.

Hypersensitivity and allergic reactions have been reported after the first dose of fluoroquinolones. Anaphylactic and anaphylactoid reactions may progress to life-threatening shock, even after the first dose. In such cases, Polimik® should be discontinued immediately and appropriate treatment (e.g., shock treatment) initiated.

Severe bullous reactions.

Cases of severe bullous reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis, have been reported with ofloxacin (see section 4.8). Patients should be advised to seek immediate medical attention before continuing treatment with Polymyxin® if skin and/or mucous membrane reactions occur.

Diseases caused by Clostridium difficile.

Diarrhea, particularly severe, persistent and/or haemorrhagic, during or after treatment with ofloxacin (including several weeks after treatment) may be a symptom of pseudomembranous colitis [Clostridium difficile-associated disease (CDAD)]. CDAD can range in severity from mild to life-threatening; the most severe form is pseudomembranous colitis (see section 4.8). It is therefore important to consider this diagnosis in patients who develop serious diarrhoea during or after treatment with Polymyxin B. If pseudomembranous colitis is suspected, the drug should be discontinued immediately and appropriate specific antibiotic therapy (e.g. oral vancomycin, oral teicoplanin or metronidazole) should be initiated immediately. Medicinal products that inhibit intestinal motility are contraindicated in this clinical situation.

Tendinitis and tendon ruptures.

Tendinitis and tendon ruptures (especially of the Achilles tendon), sometimes bilateral, may occur within 48 hours of starting treatment with quinolones or fluoroquinolones or even several months after stopping therapy. Elderly patients, patients with impaired renal function or organ transplant recipients, and those taking corticosteroids are at higher risk of developing tendonitis and tendon ruptures. Therefore, concomitant use of corticosteroids with Polymic® should be avoided. At the first signs of tendinitis (e.g. inflammation and swelling accompanied by pain), the drug should be discontinued and alternative treatment should be considered. The affected limb(s) should be treated appropriately (e.g. immobilization). Corticosteroids should not be used if signs of tendinopathy occur.

Patients with renal impairment.

When using the drug Polymic®, it is necessary to maintain adequate hydration (patients should consume sufficient water) to prevent crystalluria.

Patients with impaired renal function should be prescribed the drug with caution (the average daily dose should not be exceeded) and laboratory parameters of renal function should be monitored. Since ofloxacin is excreted mainly by the kidneys, patients with impaired renal function should adjust the dose of ofloxacin.

Patients with liver dysfunction.

Polimik® should be used with caution in patients with impaired liver function due to the possibility of liver damage as a result of its administration. Cases of fulminant hepatitis leading to liver failure (including fatal cases) have been reported during treatment with fluoroquinolones. Patients should be advised to discontinue treatment and consult a doctor if signs and symptoms of liver disease such as anorexia, jaundice, dark urine, itching or abdominal pain occur (see section "Adverse Reactions").

Patients with severe liver damage (cirrhosis) should not exceed the average daily dose.

Very rare cases of QT prolongation have been reported with fluoroquinolones. Polimik® is contraindicated in patients with QT prolongation (see section "Contraindications"). The drug should be avoided in patients with risk factors for QT prolongation, in elderly patients, in patients with electrolyte imbalance (hypokalemia, hypomagnesemia) and in patients with heart disease (heart failure, myocardial infarction, bradycardia).

Patients receiving vitamin K antagonists.

Since increased coagulation tests (PT/INR) and/or bleeding may occur in patients receiving fluoroquinolones, including ofloxacin, in combination with a vitamin K antagonist (e.g. warfarin), coagulation tests should be monitored (see section 4.5).

Prevention of photosensitization.

Photosensitivity has been reported with ofloxacin (see section 4.8). To prevent photosensitivity, patients are advised to avoid exposure to strong sunlight or artificial UV sources (e.g., artificial ultraviolet lamps, solariums) during and for 48 hours after discontinuation of Polymic® therapy.

Superinfection.

As with other antibiotics, the use of ofloxacin, especially long-term use, may lead to the growth of resistant microorganisms, therefore, during treatment, the patient's condition should be periodically checked. If a secondary infection develops during therapy with the drug Polymic®, appropriate measures should be taken.

Resistance of some strains of Pseudomonas aeruginosa.

During treatment with ofloxacin, as with other drugs from the fluoroquinolone group, resistance in some strains of Pseudomonas aeruginosa can develop quite rapidly.

Methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is very likely to be resistant to fluoroquinolones, including ofloxacin. Therefore, Polimik® is not recommended for the treatment of infections in which MRSA is known or suspected to be the causative agent, unless laboratory tests have confirmed the causative agent's susceptibility to ofloxacin (and the use of antibacterial agents usually recommended for the treatment of infections caused by MRSA is considered inappropriate).

Infections caused by Escherichia coli (E. coli).

Fluoroquinolone resistance in E. coli (the most common cause of urinary tract infections) varies across the European Union. When prescribing fluoroquinolones, the local prevalence of fluoroquinolone resistance in E. coli should be taken into account.

Pneumonia caused by pneumococci or mycoplasmas, tonsillar angina caused by
β-hemolytic streptococci.

Polymic® is not the drug of choice for the treatment of pneumonia caused by pneumococci or mycoplasmas, or infections caused by β-hemolytic streptococci.

Infections caused by Neisseria gonorrhoeae.

Due to the increasing resistance of N. gonorrhoeae, Polymic® should not be used as empirical antibacterial therapy for suspected gonococcal infection (gonococcal urethritis, pelvic inflammatory disease and epididymo-orchitis), unless the pathogen has been identified and its sensitivity to ofloxacin has been confirmed. If clinical improvement has not been achieved after 3 days of treatment, therapy should be reviewed.

Dysglycemia.

Changes in blood glucose levels (including both hyperglycemia and hypoglycemia) have been reported with the use of quinolones, especially in diabetic patients receiving concomitant oral hypoglycemic agents (e.g. glibenclamide) or insulin. Cases of hypoglycemic coma have been reported. Blood sugar levels should be monitored in diabetic patients (see section 4.8).

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.

Visual impairment.

If any visual disturbances occur, you should immediately consult an ophthalmologist.

Impact on laboratory test results.

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

Aortic aneurysm/dissection, regurgitation/heart valve 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.

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

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

- risk factors for aortic aneurysm/dissection: vascular diseases such as Takayasu arteritis or giant cell arteritis, atherosclerosis, Sjögren's syndrome;

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

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

Patients should seek emergency medical attention immediately if they experience severe abdominal, chest, or back pain.

Patients should be advised to seek immediate medical attention if they experience acute shortness of breath, new onset of palpitations, or swelling of the abdomen or lower extremities.

Medicines that contain magnesium, aluminum, iron, zinc, and sucralfate.

It is not recommended to take Polymic® within 4 hours of taking medications containing magnesium, aluminum, iron, zinc, and sucralfate.

Features of use associated with ornidazole.

Blood disorders.

In patients with a history of blood disorders, it is recommended to monitor leukocyte levels, especially during repeated courses of treatment.

Central or peripheral nervous system disorders.

Exacerbation of central or peripheral nervous system disorders may occur during ornidazole therapy. Polimik® is contraindicated in patients with central nervous system disorders, including multiple sclerosis (see Contraindications).

In the event of peripheral neuropathy, impaired coordination of movements (ataxia), dizziness or loss of consciousness, the drug should be discontinued.

Candidiasis.

Exacerbation of candidiasis is possible, which will require appropriate treatment.

Hemodialysis.

In the case of hemodialysis, it is necessary to take into account the reduction in the half-life of ornidazole and prescribe additional doses of the drug before or after hemodialysis.

Lithium therapy.

Lithium and electrolyte concentrations, as well as creatinine levels, should be monitored when using medications containing lithium salts.

Patients with hepatic impairment

Use with caution in patients with impaired liver function.

Alcohol consumption.

During treatment with the drug Polymic®, alcoholic beverages should not be consumed.

Excipients.

The drug Polimik® contains the azo dye sunset yellow FCF (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding

The drug Polimik® is contraindicated during pregnancy or breastfeeding (see the section "Contraindications").

If it is necessary to use the drug, breastfeeding should be discontinued for the period of therapy.

Ability to influence reaction speed when driving vehicles or other mechanisms

Since the use of the drug Polimik® may cause adverse reactions that affect the speed of psychomotor reactions, you should refrain from driving vehicles and mechanisms during therapy with the drug.

Method of administration and doses

Polymic should be taken orally, regardless of meals, with sufficient water. The tablets should not be chewed.

The dose of the drug and the duration of treatment depend on the sensitivity of microorganisms, the severity and type of infectious process.

The dose for adults is 1 tablet 2 times a day for up to 5 days. If necessary, continue treatment with ofloxacin tablets, taking into account official recommendations for its use.

Children

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

Overdose

Symptoms.

Associated with ofloxacin.

The most important expected signs of acute ofloxacin overdose are central nervous system symptoms, including confusion, dizziness, impaired consciousness, seizures, QT prolongation, and gastrointestinal reactions such as nausea and erosive mucosal lesions.

During post-marketing studies, central nervous system adverse reactions such as confusion, seizures, hallucinations, and tremor were observed.

Associated with ornidazole.

Overdose may cause loss of consciousness, headache, dizziness, tremors, convulsions, peripheral neuritis, dyspeptic disorders, and increased symptoms of other adverse reactions.

In case of overdose, appropriate measures are recommended, such as gastric lavage, administration of adsorbents and sodium sulfate, if possible, within the first 30 minutes after overdose. Antacids are recommended to protect the gastric mucosa. Ofloxacin fractions can be removed from the body by hemodialysis.

Peritoneal dialysis and continuous ambulatory peritoneal dialysis are not effective in removing ofloxacin from the body. There is no specific antidote to the drug. The elimination of ofloxacin can be enhanced by forced diuresis.

In case of overdose, symptomatic treatment should be applied. ECG monitoring is necessary due to possible prolongation of the QT interval.

In case of convulsions, diazepam should be used.

Adverse reactions

Infections and invasions: fungal infections, resistance of pathogenic microorganisms, proliferation of other resistant microorganisms, exacerbation of candidomycosis.

Immune system disorders: hypersensitivity reactions, including manifestations of skin allergic reactions; anaphylactic/anaphylactoid reactions; shock, including anaphylactic/anaphylactoid shock; angioedema (including swelling of the tongue, larynx, pharynx, swelling/swelling of the face); Stevens-Johnson syndrome; Lyell's syndrome; drug dermatitis; vasculitis, which in exceptional cases can lead to necrosis; pneumonitis.

Skin and subcutaneous tissue disorders: itching, skin rashes including urticaria, bullous rash, pustular rash, erythema multiforme, vascular purpura, acute generalized exanthematous pustulosis; hyperhidrosis; photosensitivity reactions, photosensitivity, hypersensitivity in the form of solar erythema; skin discoloration; nail exfoliation, skin hyperemia, exfoliative dermatitis.

Cardiovascular system**: hot flashes; hypotension, collapse; tachycardia, ventricular arrhythmias, torsades de pointes type arrhythmia, ventricular flutter-fibrillation (observed mainly in patients with risk factors for QT interval prolongation), prolongation of the QT interval on the electrocardiogram (see sections "Special instructions" and "Overdose"); cerebral thrombosis; cardiovascular disorders.

From the blood and lymphatic system: neutropenia, leukopenia, anemia, hemolytic anemia, eosinophilia, thrombocytopenia, pancytopenia, agranulocytosis, bone marrow suppression, blood dyscrasia such as medullary aplasia, petechiae, ecchymosis (bruising), prolonged prothrombin time, thrombocytopenic purpura, bone marrow effects, bone marrow suppression.

From the respiratory system: cough, shortness of breath (dyspnea), including severe; bronchospasm, severe wheezing, stridor, nasopharyngitis, pharyngitis; allergic pneumonitis, pulmonary edema.

Gastrointestinal: anorexia (loss of appetite); change in taste sensations (dysgeusia), taste disturbance, ageusia, including metallic taste in the mouth, dry mouth, soreness of the oral mucosa, increased salivation, coated tongue; stomatitis, dyspepsia, nausea, vomiting, heartburn, gastralgia (abdominal pain), pain or cramping in the abdomen; epigastric pain; diarrhea, frequent loose stools, gastrointestinal distress, constipation, enterocolitis, sometimes hemorrhagic enterocolitis, flatulence, dysbacteriosis, pseudomembranous colitis, pancreatitis.

Hepatobiliary system: manifestations of hepatotoxicity, including changes in liver function tests; increased levels of liver enzymes [(alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gamma-glutamyltransferase (GGT) and/or alkaline phosphatase (ALP)], increased levels of bilirubin in the blood, jaundice, including cholestatic jaundice; hepatitis (sometimes severe), severe liver damage, including cases of acute liver failure, sometimes fatal, mainly in patients with impaired liver function