Linezolidin film-coated tablets 600 mg blister No. 10

Instructions Linezolidin film-coated tablets 600 mg blister No. 10

Composition

active ingredient: linezolid;

1 tablet contains linezolid in terms of 100% substance 600 mg;

Excipients: microcrystalline cellulose; corn starch; hydroxypropyl cellulose; sodium starch glycolate (type A); magnesium stearate; coating mixture "Aquarius Preferred HSP BPP218011", containing hydroxypropyl methylcellulose, titanium dioxide (E 171), copovidone, polydextrose, polyethylene glycol, medium chain triglycerides.

Dosage form

Film-coated tablets.

Main physicochemical properties: film-coated tablets of white or almost white color, oval shape, with a biconvex surface.

Pharmacotherapeutic group

Antibacterials for systemic use. ATX code J01X X08.

Pharmacological properties

Pharmacodynamics

General characteristics.

Linezolid is a synthetic substance belonging to a new class of antimicrobial agents - oxazolidinones. It exhibits in vitro activity against aerobic Gram-positive bacteria and anaerobic microorganisms. Linezolid selectively inhibits bacterial protein synthesis through a unique mechanism of action. It binds directly to bacterial ribosomes (23S of 50S subunits) and prevents the formation of a functional 70S initiation complex (an important component of the translation process).

The prevalence of acquired resistance may vary geographically and over time for individual species, therefore it is advisable to rely on local information on resistance patterns, particularly in the treatment of severe infections. Expert advice should be sought when the local prevalence of resistance is such that the benefit of the medicinal product in at least some types of infections is questionable.

Sensitive microorganisms

Gram-positive aerobic microorganisms: Enterococcus faecalis, Enterococcus faecium*, Staphylococcus aureus*, coagulase-negative staphylococci, Streptococcus agalactiae*, Streptococcus pneumoniae*, Streptococcus pyogenes*, Group C streptococci, Group G streptococci.

Gram-positive anaerobic microorganisms: Clostridium perfringens, Peptostreptococcus anaerobius, Peptostreptococcus species.

Resistant microorganisms: Haemophilus influenza, Moraxella catarrhalis, Neisseria species, Enterobacteriaceae, Pseudomonas species.

*Clinical efficacy has been demonstrated for susceptible strains according to the approved indications.

Although linezolid demonstrates some in vitro activity against Legionella, Chlamydia pneumoniae, and Mycoplasma pneumoniae, there are insufficient data to support clinical efficacy in these cases.

Cross-resistance

The mechanism of action of linezolid differs from that of other classes of antibiotics. In vitro studies of clinical strains (methicillin-resistant staphylococci, vancomycin-resistant enterococci, and penicillin- and erythromycin-resistant streptococci) show that linezolid is generally active against microorganisms resistant to one or more other classes of antimicrobial agents.

Resistance to linezolid is associated with point mutations in 23S rRNA.

Pharmacokinetics

The drug Linezolid contains linezolid, which is a biologically active substance and is metabolized to inactive derivatives.

Absorption

Linezolid is extensively absorbed after oral administration. Peak plasma concentrations are reached approximately 1-2 hours after administration, and the absolute bioavailability of the drug is approximately 100%. Therefore, linezolid can be administered orally or intravenously without dose adjustment. Linezolid can be administered without regard to food intake. The time to peak concentration is increased from 1.5 to 2.2 hours and Cmax is decreased by approximately 17% when linezolid is administered with a high-fat meal. However, the total exposure, as assessed by AUC0-¥, is similar in both cases.

Distribution

Pharmacokinetic studies have shown that linezolid is rapidly distributed into well-perfused tissues. Approximately 31% of linezolid is bound to plasma proteins, and this is independent of drug concentration. The volume of distribution of linezolid at steady state in healthy adult volunteers averages 40–50 L. After multiple administration, linezolid concentrations were determined in various fluids in a limited number of volunteers in phase 1 studies. The saliva to plasma ratio of linezolid was 1.2:1, and the sweat to plasma ratio was 0.55:1.

Metabolism

Linezolid is primarily metabolized by oxidation of the morpholine ring to form two inactive ring-opened carboxylic acid derivatives: the aminoethoxyacetic acid metabolite (A) and the hydroxyethylglycine metabolite (B). Metabolite A is thought to be formed enzymatically, while the formation of metabolite B is mediated by a non-enzymatic mechanism involving chemical oxidation under in vitro conditions. In vitro studies have shown that linezolid is minimally metabolized, with possible involvement of the human cytochrome P450 system. However, the metabolic pathways of linezolid are not fully understood.

Non-renal clearance accounts for approximately 65% of the total clearance of linezolid. At steady state, approximately 30% of the dose is recovered in the urine as linezolid, 40% as metabolite B, and 10% as metabolite A. The mean renal clearance of linezolid is 40 mL/min, indicating tubular reabsorption. Linezolid is virtually undetectable in the feces, while approximately 6% of the dose is recovered in the feces as metabolite B and 3% as metabolite A. A slight non-linearity in clearance was observed with increasing linezolid doses, which is likely due to lower renal and non-renal clearance of the drug at higher concentrations. However, this difference in clearance was small and did not affect the apparent half-life.

Patients with Renal Impairment. The pharmacokinetics of linezolid are not altered in patients with any degree of renal impairment; however, the two major metabolites of linezolid accumulate in patients with renal impairment, with accumulation increasing in patients with greater severity of renal dysfunction. The pharmacokinetics of linezolid and its two metabolites have also been studied in patients with end-stage renal disease (ESRD) undergoing hemodialysis. In the ESRD study, 14 patients received 600 mg of linezolid every 12 hours for 14.5 days. Since similar plasma concentrations of linezolid were achieved regardless of renal function, no dosage adjustment is recommended for patients with renal impairment. However, given the lack of information on the clinical significance of accumulation of the major metabolites, the use of linezolid in patients with renal insufficiency should be considered in light of the potential risk of accumulation of these metabolites. Both linezolid and the two metabolites are removed by haemodialysis. There is no information on the effect of peritoneal dialysis on the pharmacokinetics of linezolid.

Patients with hepatic impairment. The pharmacokinetics of linezolid were not altered in 7 patients with mild to moderate hepatic impairment (Child-Pugh class A or B). Based on available data, no dose adjustment is recommended for patients with mild to moderate hepatic impairment. Pharmacokinetics in patients with severe hepatic impairment have not been evaluated.

Indication

Treatment of infections caused by susceptible strains of anaerobic or aerobic gram-positive microorganisms, including infections accompanied by bacteremia, such as:

nosocomial pneumonia; community-acquired pneumonia; complicated skin and skin structure infections, including diabetic foot infections without concomitant osteomyelitis, caused by Staphylococcus aureus (methicillin-susceptible and methicillin-resistant isolates), Staphylococcus pyogenes, or Staphylococcus agalactiae; uncomplicated skin and skin structure infections caused by Staphylococcus aureus (methicillin-susceptible isolates only) or Staphylococcus pyogenes; infections caused by enterococci, including vancomycin-resistant strains of Enterococcus faecium and faecalis.

If the causative agents of the infection include gram-negative microorganisms, the appointment of combination therapy is clinically indicated.

Contraindication

Known hypersensitivity to linezolid or any other component of the drug.

Linezolid should not be used in patients taking any medications that inhibit monoamine oxidase A and B (e.g. phenelzine, isocarboxazid, selegiline, moclobemide) or within 2 weeks of taking such medications.

Unless close monitoring of blood pressure is possible, Linezolid should not be administered to patients with the following concomitant clinical conditions or concomitant medication:

uncontrolled hypertension, pheochromocytoma, carcinoid, thyrotoxicosis, bipolar depression, schizoaffective disorder, acute episodes of dizziness; serotonin reuptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists (triptans), direct and indirect sympathomimetics (including adrenergic bronchodilators, pseudoephedrine, phenylpropanolamine), vasopressors (epinephrine, norepinephrine), dopaminergic compounds (dopamine, dobutamine), pethidine or buspirone.

Breastfeeding should be discontinued during use of the drug (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other types of interactions

Monoamine oxidase inhibitors

Linezolid is a non-selective, reversible inhibitor of monoamine oxidase (MAO). Very limited data from drug interaction studies and linezolid safety studies have been obtained on the use of linezolid in patients receiving concomitant medications that pose a risk due to MAO inhibition. Therefore, the use of linezolid in such circumstances is not recommended unless close monitoring of the patient is possible (see sections 4.3 and 4.4).

There is evidence that in healthy volunteers with normal blood pressure, linezolid enhances the increase in blood pressure caused by pseudoephedrine and phenylpropanolamine hydrochloride. Concomitant use of linezolid and pseudoephedrine or phenylpropanolamine hydrochloride leads to an increase in systolic blood pressure by an average of 30-40 mm Hg compared with an increase of 11-15 mm Hg under the influence of linezolid alone, 14-18 mm Hg under the influence of pseudoephedrine or phenylpropanolamine alone, and 8-11 mm Hg with placebo. Similar studies have not been conducted in patients with hypertension. It is recommended to carefully select doses that have a vasopressor effect, including dopaminergic drugs, to obtain the desired result when linezolid is used in combination with these drugs.

Potential serotonergic interactions

The potential for interactions between linezolid and dextromethorphan was investigated in a study in healthy volunteers. Subjects received dextromethorphan (two 20 mg doses 4 hours apart) with or without linezolid. No serotonin syndrome (confusion, delirium, restlessness, tremor, flushing, diaphoresis, hyperpyrexia) was observed in healthy subjects receiving linezolid and dextromethorphan.

Postmarketing experience: There has been one report of serotonin syndrome-like events in a patient receiving linezolid and dextromethorphan, which resolved after discontinuation of both drugs.

Cases of serotonin syndrome have been reported during clinical use of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs). Therefore, although the combined use of these agents is contraindicated (see section 4.3), the management of patients for whom treatment with both linezolid and serotonergic agents is essential is described in section 4.4.

Use in combination with tyramine-rich foods

No significant vasopressor effect was observed in patients receiving linezolid and tyramine at doses less than 100 mg. This suggests that only excessive consumption of foods and beverages high in tyramine (namely, mature cheeses, yeast extracts, undistilled alcoholic beverages, and fermented soybean products such as soy sauce) should be avoided.

Drugs metabolized by cytochrome P450

Linezolid is not metabolized by the cytochrome P450 enzyme system and does not inhibit the function of any of the clinically relevant human cytochrome P450 isoforms (1A2, 2C9, 2C19, 2D6, 2E1, 3A4). Similarly, linezolid does not induce cytochrome P450 isoenzymes in rats. Therefore, linezolid is not expected to affect the pharmacokinetics of other drugs metabolized by CYP450.

Rifampicin: The effect of rifampicin on the pharmacokinetics of linezolid was studied in 16 healthy adult male volunteers who were administered linezolid (600 mg twice daily for 2.5 days) with and without rifampicin (600 mg once daily for 8 days). Rifampicin decreased linezolid Cmax and AUC by a mean of 21% (90% CI 15, 27) and a mean of 32% (90% CI 27, 37), respectively. The mechanism of this interaction and its clinical significance are unknown.

Warfarin: When warfarin was added to linezolid therapy at steady state, a 10% decrease in mean peak MHC was observed with concomitant administration, with a 5% decrease in MHC AUC. There are insufficient data in patients receiving warfarin and linezolid concomitantly to assess the clinical significance, if any.

Antibiotics

Aztreonam: The pharmacokinetics of linezolid or aztreonam are not altered by co-administration of these drugs.

Gentamicin: The pharmacokinetics of linezolid or gentamicin are not altered by co-administration of these drugs.

In vitro studies have demonstrated additivity or indifference between linezolid and vancomycin, gentamicin, rifampin, imipenem-cilastatin, aztreonam, ampicillin, streptomycin.

Antioxidants

When using the drug simultaneously with vitamin C or vitamin E, dose adjustment of linezolid is not recommended.

Application features

Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported in some patients receiving linezolid. There is evidence that haematological parameters have returned to pre-treatment levels after discontinuation of linezolid. The risk of these effects is likely to be related to the duration of treatment. Elderly patients may be at greater risk of developing haematological abnormalities when linezolid is used compared with younger patients. Patients with severe renal impairment (whether or not undergoing dialysis) may be at increased risk of thrombocytopenia. Therefore, close monitoring of blood counts is necessary in the following patient groups: patients with pre-existing anemia, granulocytopenia, or thrombocytopenia; patients receiving concomitant medications that may lower haemoglobin levels, reduce the number of formed blood cells, or adversely affect platelet count or function; Patients with severe renal impairment Patients whose treatment lasts more than 10-14 days. Linezolid should be used in these patients only in conjunction with close monitoring of hemoglobin levels, complete blood count, and, if possible, platelet count.

If significant myelosuppression develops during treatment with linezolid, treatment should be discontinued unless continued treatment is considered essential. In such situations, close monitoring of complete blood counts and appropriate treatment strategies should be implemented.

In addition, weekly monitoring of complete blood counts (including hemoglobin, platelet count, total white blood cell count, and differential white blood cell count) is recommended in patients receiving linezolid, regardless of baseline blood counts.

In studies using an unlicensed medicinal product under a humanitarian program (compassionate use), an increased incidence of serious anemia was observed in patients receiving linezolid for 28 days (the maximum recommended duration of treatment). These patients were more likely to require blood transfusions. Cases of anemia requiring blood transfusions have also been reported in the post-marketing period. Such anemia occurred more frequently in patients receiving linezolid for more than 28 days.

Sideroblastic anemia has also been reported in the postmarketing setting. Among cases for which the time of treatment initiation was known, the majority of patients had been receiving linezolid for more than 28 days. After discontinuation of linezolid, most patients recovered completely or partially with or without treatment for anemia.

Imbalance in mortality rates in a clinical trial involving patients with catheter-related bloodstream infections caused by gram-positive pathogens

In an open-label study of patients with serious catheter-related intravascular infections, there was an increased mortality rate in the linezolid group compared with the vancomycin/dicloxacillin/oxacillin groups (78 of 363 (21.5%) vs. 58 of 363 (16.0%)). The main factor influencing the mortality rate was the presence of gram-positive infection at baseline.

Mortality rates were similar in patients with infections caused exclusively by gram-positive organisms (odds ratio 0.96; 95% confidence interval: 0.58–1.59), but in the linezolid group, the mortality rate was significantly higher (p=0.0162) in patients with any additional pathogen or no pathogens at baseline (odds ratio 2.48; 95% confidence interval: 1.38–4.46). The greatest imbalance was observed during treatment and within 7 days of discontinuation of study drug. The majority of patients in the linezolid group acquired gram-negative infections during the study and died from infections caused by gram-negative pathogens and from polymicrobial infections. Therefore, in complicated skin and soft tissue infections in patients with known or suspected concomitant infection due to Gram-negative organisms, linezolid should only be used when no other treatment options are available (see section 4.3). In such circumstances, concurrent treatment for the Gram-negative infection should be initiated.

Antibiotic-associated diarrhea and colitis, including pseudomembranous colitis and Clostridium difficile-associated diarrhea (CDAD), have been reported with nearly all antibacterial agents, including linezolid, and may range in severity from mild diarrhea to fatal colitis. Therefore, it is important to consider this diagnosis in patients who develop diarrhea during or after linezolid therapy. If antibiotic-associated diarrhea or colitis is suspected or confirmed, antibacterial agents (including linezolid) should be discontinued and appropriate therapeutic measures should be initiated immediately. In such situations, the use of agents that inhibit peristalsis is contraindicated.

Lactic acidosis

Lactic acidosis has been reported with linezolid. Patients who develop symptoms and signs of metabolic acidosis, including recurrent nausea or vomiting, abdominal pain, low bicarbonate levels, or hyperventilation, while taking linezolid should seek immediate medical attention. If lactic acidosis develops, the benefits of continued linezolid therapy should be weighed against the potential risks.

Mitochondrial dysfunction

Linezolid inhibits mitochondrial protein synthesis. This inhibition may result in adverse reactions such as lactic acidosis, anemia, and neuropathy (peripheral and optic). These events are common when the drug is used for more than 28 days.

Potential interactions causing increased blood pressure

Unless patients can be monitored for increased blood pressure, linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis and/or concomitant use of the following types of medicinal products: direct and indirect sympathomimetics (e.g. pseudoephedrine), vasopressin (e.g. epinephrine, norepinephrine), dopaminergic agents (e.g. dopamine, dobutamine).

Serotonin syndrome

Serotonin syndrome has been reported spontaneously with concomitant use of linezolid and serotonergic drugs, including antidepressants (such as selective serotonin reuptake inhibitors (SSRIs). Therefore, concomitant use of linezolid and serotonergic drugs is contraindicated (see section 4.3), unless both linezolid and the concomitant use of the serotonergic drug are essential. In such cases, the patient should be closely observed for symptoms of serotonin syndrome, such as cognitive impairment, hyperpyrexia, hyperreflexia, and incoordination. If such symptoms occur, the physician should consider discontinuing the drug. Withdrawal symptoms may occur following discontinuation of the serotonergic drug.

Peripheral neuropathy and optic neuropathy

Peripheral neuropathy and optic neuropathy, sometimes progressing to vision loss, have been reported in patients treated with linezolid, primarily in patients treated for 28 days (the maximum recommended duration of treatment).

All patients should be advised to report symptoms of visual impairment, such as changes in visual acuity, changes in color perception, blurred vision, or loss of part of the visual field. In such cases, urgent examination is recommended, with referral to an ophthalmologist if necessary. If the patient is taking linezolid for more than the recommended 28 days, he should have his vision checked regularly.

In the event of the development of peripheral neuropathy or optic neuropathy, the benefits of continued linezolid treatment should be weighed against the potential risks.

There may be an increased risk of neuropathy when linezolid is used in patients who are taking or have recently taken antibacterial drugs for the treatment of tuberculosis.

Convulsions

Cases of seizures have been reported in patients receiving linezolid therapy. In most cases, a history of seizures was reported as a risk factor. Patients should inform their physician of any history of seizures.

Monoamine oxidase inhibitors

Linezolid is a non-selective, reversible inhibitor of monoamine oxidase (MAO). However, at doses used for antibacterial therapy, it does not exhibit antidepressant effects. Very limited data from drug interaction studies and safety studies of linezolid have been obtained on the use of linezolid in patients with underlying diseases and/or concomitant medications that pose a risk of MAO inhibition. Therefore, the use of linezolid in such circumstances is not recommended unless close monitoring of the patient is possible (see sections 4.3 and 4.5).

Patients should be advised to avoid consuming large amounts of tyramine-rich foods (see section 4.5).

Hypoglycemia

Postmarketing reports have included cases of symptomatic hypoglycemia with linezolid, a nonselective, reversible MAOI, in diabetic patients receiving insulin or oral hypoglycemic agents. Some MAOIs have been associated with hypoglycemic episodes in diabetic patients receiving insulin or oral hypoglycemic agents. Although a causal relationship between linezolid and hypoglycemia has not been established, diabetic patients should be warned of the potential for hypoglycemic reactions when receiving linezolid.

If hypoglycemia occurs, a reduction in the dose of insulin or oral hypoglycemic agent or discontinuation of the oral hypoglycemic agent, insulin, or linezolid may be necessary.

Superinfection

The effect of linezolid on normal microflora has not been studied in clinical trials.

The use of antibiotics may occasionally result in overgrowth of nonsusceptible organisms. For example, approximately 3% of patients receiving linezolid at recommended doses experienced drug-related candidiasis during clinical trials. Appropriate measures should be taken if superinfection occurs during treatment.

Special patient groups

Linezolid should be used with caution in patients with severe renal impairment and only in situations where the expected benefit outweighs the theoretical risk (see section 4.2).

Linezolid should be used with caution in patients with severe hepatic impairment and only in situations where the expected benefit outweighs the theoretical risk (see section 4.2).

Sex

There is no need to adjust the dose of the drug depending on gender.

Fertility disorders

Linezolid reduced fertility and caused morphological abnormalities in sperm quality in healthy adult male rats at exposure levels approximately those expected in humans. These changes were reversible.

The potential effects of linezolid on male reproductive function are unknown.

Clinical trials

The safety and effectiveness of linezolid when taken for more than 28 days have not been established.

Patients with diabetic foot ulcers, pressure ulcers or ischemic lesions, severe burns or gangrene were not included in the studies. Accordingly, experience with linezolid in the treatment of these conditions is limited.

Emergence of drug-resistant bacteria

It is unlikely that prescribing linezolid in the absence of a diagnosed bacterial infection or for prophylactic purposes will harm the patient or increase the risk of the development of bacteria resistant to the drug.

Ability to influence reaction speed when driving vehicles or other mechanisms

Patients should be warned about the possibility of developing dizziness or visual symptoms (see sections "Special precautions for use" and "Adverse reactions") while taking linezolid and advised not to drive or operate machinery if such symptoms occur.

Use during pregnancy or breastfeeding

Use in pregnancy. There are no adequate data from the use of linezolid in pregnant women. Animal studies have shown reproductive toxicity. There is a potential risk to humans. Linezolid should not be used during pregnancy unless the expected benefit justifies the potential risk.

Use during lactation: Animal studies have shown that linezolid and its metabolites may pass into breast milk. Therefore, breastfeeding should be discontinued during treatment with the drug.

Method of administration and doses

The duration of treatment depends on the pathogen, location and severity of the infection, as well as the clinical effect of therapy.

The treatment duration recommendations below have been used in clinical trials. For some types of infections, shorter treatment durations may be appropriate, but have not been evaluated in clinical trials.

The maximum duration of treatment is 28 days. The safety and efficacy of linezolid use for periods longer than 28 days have not been studied.

No increase in recommended doses or duration of treatment is required in infections accompanied by bacteremia.

Dosage recommendations according to indications are given in the table below.

Patients who have been initiated on intravenous linezolid may be switched to oral linezolid. In this case, dose adjustment is not necessary because the oral bioavailability of linezolid is nearly 100%.

Indication

* Use the drug in a different dosage form with the possibility of an appropriate dosage

The maximum dose for adults and children should not exceed 600 mg 2 times a day.

Use in elderly patients. No dose adjustment is required.

Use in patients with renal insufficiency

No dose adjustment is necessary. Since approximately 30% of the dose is excreted within

In patients undergoing a 3-hour hemodialysis session, starting 3 hours after drug administration, linezolid should be administered after hemodialysis (see section "Pharmacological properties." "Pharmacokinetics").

Use in patients with hepatic insufficiency. No dose adjustment is required. (see section "Pharmacological properties." "Pharmacokinetics").

Children

The drug in this dosage form should be used in children over 12 years of age.

Overdose

Specific antidote is unknown.

No cases of overdose have been reported.

In case of overdose, symptomatic treatment is indicated, with measures to maintain glomerular filtration rate. Approximately 30% of the administered dose is removed during 3 hours of hemodialysis, but there are no data on the removal of linezolid during peritoneal dialysis or hemoperfusion. The two primary metabolites of linezolid are also removed by hemodialysis.

Adverse reactions

This information is based on data obtained from clinical studies in which more than 2,000 adult patients received recommended doses of the drug for up to 28 days.

The most common adverse reactions reported leading to discontinuation were headache, diarrhea, nausea, and vomiting. Approximately 3% of patients discontinued treatment due to drug-related adverse reactions.

Additional adverse reactions reported during post-marketing experience are listed below with a frequency of “not known” because the frequency cannot be estimated from the available data.

Adverse reactions reported during treatment are listed below according to the following frequency classification: very common (≥ 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000) and frequency unknown (cannot be estimated from the available data).

Infections and infestations: common – candidiasis, oral candidiasis, vaginal candidiasis, fungal infections; uncommon – vaginitis; rare – antibiotic-associated colitis, including pseudomembranous colitis*.

Blood and lymphatic system disorders: common: anemia*†; uncommon: leukopenia*, neutropenia, thrombocytopenia*, eosinophilia; rare: pancytopenia*; frequency unknown: myelosuppression*, sideroblastic anemia*.

On the part of the immune system: frequency unknown - anaphylaxis.

Metabolism and nutrition disorders: uncommon – hyponatremia; frequency unknown – lactic acidosis*.

On the part of the psyche: frequent - insomnia.

Neurological disorders: common - headache, taste perversion (metallic taste), dizziness; uncommon - convulsions*, hypoesthesia, paresthesia; frequency unknown - serotonin syndrome**, peripheral neuropathy*.

On the part of the organs of vision: infrequent - blurred vision*; rare - visual field defect*; frequency unknown - optic neuropathy*, optic neuritis*, vision loss*, change in visual sensation*, change in color perception*.

From the organs of hearing and balance: infrequently - tinnitus.

Cardiac disorders: uncommon – arrhythmia (tachycardia).

Vascular disorders: frequent - arterial hypertension; infrequent - transient ischemic attack, phlebitis, thrombophlebitis.

Gastrointestinal: common - diarrhea, nausea, vomiting, local or generalized abdominal pain, constipation, dyspepsia; uncommon - pancreatitis, gastritis, bloating, dry mouth, glossitis, frequent loose stools, stomatitis, tongue disorders or discoloration; rare - discoloration of the surface of the teeth.

On the part of the hepatobiliary system: frequent - deviations from the norm of liver function tests, increased levels of ALT, AST or alkaline phosphatase; infrequent - increased total bilirubin.

Skin and subcutaneous tissue disorders: common: pruritus, rash; uncommon: urticaria, dermatitis, excessive sweating; frequency unknown: bullous skin lesions such as Stevens-Johnson syndrome and toxic epidermal necrolysis, angioedema, alopecia.

From the kidneys and urinary system: frequent - increased blood urea nitrogen; infrequent - renal failure, increased creatinine, polyuria.

Reproductive system and breast disorders: uncommon – vulvovaginal disorders.

General disorders and administration site conditions: