Biseptol tablets 400 mg + 80 mg blister No. 20

Instructions Biseptol tablets 400 mg + 80 mg blister No. 20

Composition

active ingredients: sulfamethoxazole, trimethoprim (co-trimoxazole);

1 tablet of 100 mg/20 mg contains sulfamethoxazole 100 mg, trimethoprim 20 mg;

1 tablet 400 mg/80 mg contains sulfamethoxazole 400 mg, trimethoprim 80 mg;

excipients: potato starch, talc, magnesium stearate, polyvinyl alcohol.

Dosage form

Pills.

Main physicochemical properties:

100 mg/20 mg tablets – white tablets with a yellowish tinge, round in shape, flat on both sides, with a smooth surface, with solid edges, with a bevel, engraved with the letters “Bs” on one side;

400 mg/80 mg tablets – white tablets with a yellowish tinge, round in shape, flat on both sides, with a smooth surface, with solid edges, with a bevel, engraved on one side with a “-” line, above which are the letters “Bs”.

Pharmacotherapeutic group

Antimicrobial agents for systemic use.

ATX code J01E E01.

Pharmacological properties

Pharmacodynamics.

A combined bactericidal drug containing sulfamethoxazole, a medium-acting sulfonamide that inhibits folic acid synthesis through competitive antagonism with para-aminobenzoic acid, and trimethoprim, an inhibitor of bacterial dehydrofolic acid reductase, which is responsible for the synthesis of biologically active tetrahydrofolic acid. A mixture of these substances in a ratio of 5 to 1 is called co-trimoxazole.

The combination of components that act on one chain of biochemical transformations contributes to the synergistic antibacterial action and slower development of bacterial insensitivity.

Co-trimoxazole is active in vitro against E. coli (including enteropathogenic strains), indole-positive strains of Proteus spp. (including P. vulgaris), Morganella morganii, Klebsiella spp., Proteus mirabilis, Enterobacter sp., Hemophilus influenzae, Str. pneumoniae, Shigella flexneri, Shigella sonnei, Neisseria gonorrhoeae, Pneumocystis jirovecii.

Pharmacokinetics.

Both components of the drug are rapidly absorbed into the blood from the digestive tract. The maximum concentration of both components in serum is reached 1 - 4 hours after oral administration. Trimethoprim binds to serum proteins by 70%, sulfamethoxazole - by 44 - 62%.

The distribution of both components is different: sulfamethoxazole is distributed exclusively in the extracellular environment, trimethoprim - in all body fluids.

High concentrations of trimethoprim are found in bronchial secretions, prostate gland, and bile. Sulfamethoxazole concentrations in body fluids are somewhat lower. Both compounds appear in high concentrations in sputum, vaginal secretions, and middle ear fluid.

The volume of distribution of sulfamethoxazole is 0.36 l/kg, and of trimethoprim is 2.0 l/kg.

Both components are metabolized in the liver: sulfamethoxazole - by acetylation and binding to glucuronic acid, trimethoprim - by oxidation and hydroxylation.

It is excreted mainly by the kidneys by filtration and active tubular secretion.

The concentration of active compounds in urine is significantly higher than in blood. Within 72 hours, 84.5% of the administered dose of sulfamethoxazole and 66.8% of trimethoprim are excreted in urine.

The half-life is 10 hours for sulfamethoxazole and 8-10 hours for trimethoprim. In renal failure, the half-life of both components is prolonged.

Sulfamethoxazole and trimethoprim pass into breast milk and enter the fetal circulation.

Children and adolescents

The pharmacokinetics of both components of the drug Biseptol® (trimethoprim and sulfamethoxazole) in children and adolescents with normal renal function depend on age. A decrease in the rate of elimination of trimethoprim and sulfamethoxazole was noted in children of the first two months of life, but then the rate of elimination and total clearance of both trimethoprim and sulfamethoxazole increases, and the half-life decreases. Such changes in pharmacokinetics are most pronounced in children aged 1.7 to 24 months and decrease with age when compared with younger children (1 to 3.6 years), children aged 7.5 to 10 years and adults (see section "Method of administration and dosage").

Indication

Use for the treatment of infections caused by pathogenic microorganisms sensitive to the drug, in cases where the benefit of such treatment outweighs the possible risk; it is necessary to decide on the possibility of using only one antibacterial agent. When deciding to prescribe the drug Biseptol®, it is necessary to take into account official recommendations on the appropriate use of antibacterial agents.

Infections of the ENT organs and respiratory tract: acute and chronic bronchitis, bronchiectasis, pneumonia (including that caused by Pneumocystis jirocecii), pharyngitis, tonsillitis (in infections caused by group A β-hemolytic streptococci, the eradication rate is not entirely sufficient), sinusitis, otitis media.

Kidney and urinary tract infections: acute and chronic cystitis, pyelonephritis, urethritis, prostatitis, soft chancre.

Other bacterial infections: acute and chronic osteomyelitis, brucellosis, nocardiosis, actinomycosis, toxoplasmosis, South American blastomycosis.

Contraindication

– Hypersensitivity to trimethoprim and sulfamethoxazole (including sulfonamide derivatives, sulfonylurea antidiabetic agents, and thiazide diuretics) and excipients of the drug.

– Acute hepatitis, liver dysfunction, severe liver failure, including diagnosed liver parenchymal damage, porphyria.

– Blood diseases, hematopoiesis disorders, severe hematological disorders, megaloblastic anemia caused by folic acid deficiency, glucose-6-phosphate dehydrogenase deficiency (threat of hemolysis);

– Severe renal failure, characterized by creatinine clearance less than 15 ml/min, if it is not possible to determine the concentration of the drug in the blood plasma (except in cases of hemodialysis).

– The drug is contraindicated in patients undergoing chemotherapy.

– The drug should not be prescribed in combination with dofetilide.

- Children under 6 years of age (for this dosage form).

Interaction with other medicinal products and other types of interactions

Laboratory tests: Trimethoprim may interfere with the results of serum/plasma creatinine determinations using the alkaline picrate reaction. This may result in a 10% increase in serum/plasma creatinine concentration. Creatinine clearance is reduced: renal tubular secretion of creatinine is reduced from 23% to 9%, while glomerular filtration remains unchanged.

Nonsteroidal anti-inflammatory drugs, antidiabetic sulfonylurea derivatives, diphenin,

Indirect anticoagulants, barbiturates increase the risk of side effects.

Ascorbic acid increases crystalluria.

Patients using Biseptol® and cyclosporine after kidney transplantation may experience reversible deterioration of renal function, manifested by an increase in creatinine levels and, probably, due to the action of trimethoprim.

Trimethoprim has a low affinity for human dehydrofolate reductase, but may increase the toxicity of methotrexate, especially in the presence of other risk factors: old age, hypoalbuminemia, impaired renal function, bone marrow suppression. This side effect of the drug may occur especially when methotrexate is used in high doses. It is recommended to treat such patients with folic acid or calcium folinate to prevent effects on hematopoiesis.

Cases of pancytopenia have been described in patients using trimethoprim and methotrexate.

Co-trimoxazole increases the concentration of the free fraction of methotrexate in serum by displacing it from protein binding.

Biseptol® may potentiate the effects of drugs that are metabolized by CYP2C8 (e.g. pioglitazone, repaglinide, rosiglitazone, paclitaxel, amiodarone, dapsone, repaglinidine, rosiglitazone, and pioglitazone) or CYP2C9 (e.g. glipizide and glyburide) or that are excreted by the kidneys via OCT2 (e.g. metformin), which increases the risk of hypoglycemia. Additional monitoring of blood glucose levels may be required.

Paclitaxel and amiodarone have a narrow therapeutic index. If a patient is receiving paclitaxel or amiodarone, consideration should be given to using an alternative antibiotic.

Both dapsone and Biseptol® can cause methemoglobinuria. Patients receiving dapsone in combination with Biseptol® should be monitored for methemoglobinuria. Alternative treatments should be used whenever possible.

Zidovudine: In some cases, the concomitant use of co-trimoxazole and zidovudine increases the risk of hematological disorders caused by co-trimoxazole. If co-trimoxazole and zidovudine are necessary, blood counts should be monitored.

Warfarin: Co-trimoxazole has been shown to enhance the anticoagulant activity of warfarin by stereoselectively inhibiting its metabolism. Sulfamethoxazole may displace warfarin from its binding to plasma albumin in vitro. Therefore, careful monitoring of anticoagulant therapy is advisable during treatment with co-trimoxazole.

In patients taking indomethacin, the concentration of sulfamethoxazole in the blood may increase. One case of toxic delirium has been described after simultaneous administration of Biseptol® and amantadine.

When co-trimoxazole is used simultaneously with drugs that form cations in physiological pH and are partially excreted by the kidneys by active secretion (e.g. procainamide, amantadine), competitive inhibition of this process may occur, which may lead to an increase in the plasma concentration of one or both drugs.

Rifampicin: Concomitant administration of co-trimoxazole and rifampicin for one week has been shown to reduce the half-life of trimethoprim. However, this is not of significant clinical significance.

In elderly patients, the combination of co-trimoxazole with some diuretics, especially thiazides, increases the risk of thrombocytopenia with or without purpura.

Co-trimoxazole may increase serum digoxin concentrations, especially in elderly patients.

When used simultaneously with tricyclic antidepressants, the activity of the latter decreases.

The drug reduces the reliability of oral contraception, therefore patients should be advised to use additional contraceptive measures during treatment with Biseptol®.

The drug inhibits the metabolism of phenytoin: in individuals taking both drugs, the half-life of phenytoin increases by approximately 39% and the clearance of phenytoin decreases by approximately 27%.

When co-administered with pyrimethamine, a drug used for malaria prophylaxis, at doses above 25 mg/week, patients may develop megaloblastic anemia.

Lamivudine: Co-administration of trimethoprim and sulfamethoxazole 800 mg + 160 mg (co-trimoxazole) increases the exposure of lamivudine by 40% due to the trimethoprim content. Lamivudine does not affect the pharmacokinetics of trimethoprim or sulfamethoxazole.

Hyperkalemia: Caution should be exercised in patients taking any other medicinal products that may cause hyperkalemia, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and potassium-sparing diuretics such as spironolactone. Concomitant use of trimethoprim-sulfamethoxazole (co-trimoxazole) with these may result in clinically significant hyperkalemia.

Folinic acid: Supplementation with folinic acid has been shown to affect the antimicrobial efficacy of trimethoprim-sulfamethoxazole. This has been observed in the prevention and treatment of pneumonia caused by Pneumocystis jirovecii.

Azathioprine: There have been conflicting clinical reports of interactions between azathioprine and trimethoprim-sulfamethoxazole resulting in serious hematological disorders.

Application features

Rare cases of life-threatening complications associated with the use of sulfonamides have been described, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, aplastic anemia, agranulocytosis, other blood disorders, and respiratory tract hypersensitivity.

Life-threatening skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in association with the use of sulfamethoxazole.

Patients should be informed about the subjective and objective symptoms of skin reactions and the need for close monitoring. The highest risk of serious skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis) is observed in the first weeks of treatment.

Treatment with Biseptol® should be discontinued if subjective or objective symptoms of Stevens-Johnson syndrome or toxic epidermal necrolysis (such as sudden development of skin rashes, often with blisters, or lesions of the mucous membranes) appear (see section "Adverse reactions").

The best results in treating Stevens-Johnson syndrome or toxic epidermal necrolysis are seen when early diagnosis is made and the drug that caused the reaction is immediately discontinued. Immediate discontinuation of the drug improves the prognosis.

If a patient develops Stevens-Johnson syndrome or toxic epidermal necrolysis during treatment with Biseptol®, this medicine should not be prescribed in the future.

If a skin rash or any other adverse reaction occurs (including sore throat, fever, joint pain, pallor, purpura, jaundice that cannot be explained by other causes), the drug should be discontinued. Cough, shortness of breath and the development of pulmonary infiltrates may also be signs of a hypersensitivity reaction. Caution should be exercised when using the drug in patients with a history of severe allergic reactions or bronchial asthma.

Except in exceptional cases, Biseptol® should not be administered to patients with serious persistent changes in the cellular composition of the blood. The drug has occasionally been used in patients receiving cytotoxic agents for the treatment of leukemia, with no signs of side effects on the bone marrow or peripheral blood.

Due to the possibility of hemolysis, Biseptol® should not be prescribed to patients with certain hemoglobinopathies (Hb-Zurich, Hb-Cologne), except in cases of urgent need and only in minimal doses.

Long-term treatment with the drug is not recommended. Treatment of elderly patients should not be prolonged. Elderly patients are at increased risk of kidney or liver damage, severe skin reactions, bone marrow suppression (including blood cell formation), and thrombocytopenia with or without purpura when treated with Biseptol®. Concomitant use of diuretics increases the risk of bleeding.

Trimethoprim disrupts phenylalanine metabolism, but with an appropriate diet, it does not affect the condition of patients with phenylketonuria.

As with any sulfonamide, caution should be exercised in patients with porphyria and thyroid dysfunction. Patients with slow acetylation metabolism are more likely to develop idiosyncrasy to sulfonamides. with caution due to possible effects on antimicrobial efficacy (see section "Interaction with other medicinal products and other forms of interaction").

Biseptol® should be used with caution in patients with impaired liver or kidney function, folic acid deficiency (e.g. elderly patients, alcoholism, patients treated with anticonvulsants, patients with malabsorption syndrome or malnourished patients) and in cases of impaired hematopoiesis. Elderly patients, as well as patients with probable folic acid deficiency, should consider additional folic acid administration during treatment with the drug.

To prevent crystalluria and renal tubular obstruction, patients should consume sufficient fluids (at least 1.5 liters per day). The risk of crystalluria increases with malnutrition.

With longer treatment, it is necessary to carefully monitor the blood picture, liver and kidney function. To reduce hematological effects during treatment, folic acid (5 - 10 mg/day) can be added without the risk of any reduction in the antibacterial effects of the drug.

Caution should be exercised when prescribing Biseptol® to patients with X-linked mental retardation, as folic acid deficiency may lead to exacerbation of psychomotor disorders associated with the disease.

In AIDS patients who use Biseptol® in connection with pneumocystis infection, the following symptoms more often occur: rash, fever, leukopenia, increased aminotransferase levels, hyperkalemia and hyponatremia.

Concomitant use of drugs that cause hyperkalemia, including co-trimoxazole, in combination with spironolactone may lead to severe hyperkalemia.

During treatment, direct sunlight should be avoided or protective clothing and/or sunscreen should be used during treatment due to photosensitivity.

Pseudomembranous colitis may develop when taking co-trimoxazole (as well as when taking other antibacterial agents).

The course of the disease can range from mild to life-threatening. Therefore, the correct diagnosis of this disease in patients who develop diarrhea while taking an antibacterial drug is important. Treatment with antibacterial drugs affects the physiological flora of the colon and can cause an excessive increase in the number of anaerobic bacilli. Toxins produced by Clostridium difficile are one of the main causes of colitis.

In mild cases of pseudomembranous colitis, discontinuation of the drug is usually sufficient. In moderate to severe cases, patients should be given fluids, electrolytes, protein, and antibiotics active against Clostridium difficile (metronidazole or vancomycin). Drugs that inhibit peristalsis or other antidiarrheal drugs should not be given.

Prolonged treatment may result in overgrowth of non-susceptible organisms and fungi. In the event of superinfection, appropriate treatment should be initiated immediately.

Subject to exclusion of other possible causes, the use of the drug is associated with metabolic acidosis. If metabolic acidosis is suspected, careful monitoring of the patient is recommended.

The combination of antibiotics with co-trimoxazole should only be used in cases where, in the opinion of the physician, the benefit of treatment outweighs the potential risk. The possibility of using a single effective antibacterial drug should be considered.

Effect on laboratory test results: Trimethoprim may interfere with the results of enzymatic assays of methotrexate in serum, but does not affect the results of radioimmunoassays.

Co-trimoxazole may increase the results of the Jaffe basic picrate test for creatinine by approximately 10%.

Respiratory toxicity

Very rare cases of severe respiratory toxicity, sometimes progressing to acute respiratory distress syndrome (ARDS), have been reported during treatment with sulfamethoxazole/trimethoprim. The development of pulmonary manifestations such as cough, fever and dyspnoea in association with radiographic evidence of pulmonary infiltrates and deterioration of pulmonary function may be precursors of ARDS. In such circumstances, sulfamethoxazole/trimethoprim should be discontinued and appropriate treatment should be initiated.

Very rare cases of hemophagocytic lymphohistiocytosis have been reported in patients receiving sulfamethoxazole/trimethoprim. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome of pathological immune activation characterized by clinical signs and symptoms of excessive systemic inflammation (e.g., fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, high serum ferritin, cytopenias, and hemophagocytosis). Patients who develop early signs of pathological immune activation should be evaluated promptly. If hemophagocytic lymphohistiocytosis is diagnosed, sulfamethoxazole/trimethoprim should be discontinued.

Use during pregnancy or breastfeeding

Biseptol® should not be used during pregnancy and breastfeeding.

Use during pregnancy

There are no reliable data on the use of trimethoprim-sulfamethoxazole in pregnant women. Case-control studies have shown a possible association between the effects of folic acid antagonists and the occurrence of fetal damage.

Trimethoprim is a folic acid antagonist, and in animal studies, both active substances caused fetal abnormalities.

Co-trimoxazole should not be used during pregnancy, especially in the first trimester, unless clearly necessary. If co-trimoxazole is used during pregnancy, additional folic acid supplementation should be considered.

Sulfamethoxazole competes with bilirubin for the binding site of plasma albumin. When the drug is administered to the mother before delivery, significant concentrations of the drug obtained from the mother are retained in the newborn for several days, and there is also a risk of bilirubin precipitation or increased hyperbilirubinemia, which is theoretically associated with the risk of developing kernicterus. This is especially true for newborns at increased risk of hyperbilirubinemia, such as premature infants and infants with glucose-6-phosphate dehydrogenase deficiency.

Use during breastfeeding

The components of co-trimoxazole (trimethoprim and sulfamethoxazole) pass into breast milk. Co-trimoxazole should be avoided in late pregnancy and during breastfeeding, and in mothers or infants with hyperbilirubinemia or at risk of developing it. Co-trimoxazole should also be avoided in infants under eight weeks of age due to the risk of neonatal hyperbilirubinemia.

Co-trimoxazole should not be used in infants during the first 6 weeks of life.

Ability to influence reaction speed when driving vehicles or other mechanisms

The drug does not cause a decrease in psychophysical activity and the ability to drive vehicles and operate machinery.

If side effects from the nervous system develop during treatment (dizziness, headache, seizures, nervousness, fatigue), which may lead to a decrease in the speed of psychomotor reactions, you should avoid driving and working with complex mechanisms.

Method of administration and doses

Adults and children over 12 years of age. The usual initial dose is 2 tablets of Biseptol® 400 mg / 80 mg or 8 tablets of Biseptol® 100 mg / 20 mg 2 times a day (morning and evening). Take after meals, with plenty of fluids. In severe infections, higher daily doses may be prescribed - up to 3 tablets of Biseptol® 400 mg / 80 mg or 12 tablets of Biseptol® 100 mg / 20 mg 2 times a day. For maintenance therapy lasting more than 14 days, it is recommended to take 1 tablet of Biseptol® 400 mg / 80 mg or 4 tablets of Biseptol® 100 mg / 20 mg 2 times a day.

Children 6–12 years of age. The recommended daily dose for children is 6 mg of trimethoprim and 30 mg of sulfamethoxazole per kg of body weight. This dose should be divided into two doses.

The recommended daily dose for children aged 6 to 12 years is 1 tablet of Biseptol® 400 mg / 80 mg or 4 tablets of Biseptol® 100 mg / 20 mg 2 times a day.

It is recommended to prescribe other dosage forms of co-trimoxazole (suspension) to children under 6 years of age.

The duration of treatment for acute infections, with the exception of gonorrhea, should be at least 5 days or 2 more days after the symptoms of the disease disappear. A three-day course of treatment may be sufficient for women with uncomplicated acute cystitis. However, children with this disease are recommended to use the drug for 5-7 days. In acute brucellosis, the duration of treatment should be at least 4 weeks, and in nocardiosis - even longer (6-8 tablets of Biseptol® 400 mg / 80 mg for 3 months).

Treatment of pneumonia caused by Pneumocystis jirovecii in adults and children:

The recommended dose of co-trimoxazole for individuals with confirmed inflammation is 90–120 mg/kg body weight per day, to be taken every 6 hours for 21 days.

Table 1. Maximum doses of Biseptol® depending on body weight of patients with pneumonia caused by Pneumocystis jirovecii.

The dosing regimen for the treatment of Pneumocystis jirovecii pneumonia (see above) can be used for the prevention and treatment of toxoplasmosis.

For uncomplicated gonorrhea, a one-day course of treatment is possible - 5 tablets of Biseptol® 400 mg / 80 mg 2 times a day (morning and evening) or a two-day course of treatment - 4 tablets of Biseptol® 400 mg / 80 mg 2 times a day.

Prevention of infections caused by Pneumocystis jirovecii

Adults and children over 12 years of age: 960 mg of co-trimoxazole (8 tablets of Biseptol® 120 or 2 tablets of Biseptol® 480) once daily for 7 days. In case of poor tolerance, a reduction in the daily dose to 480 mg may be considered.

Children 6–12 years: 900 mg co-trimoxazole/m2 body surface area per day in two equal doses every 12 hours for 3 consecutive days.

Table 2. Doses of Biseptol® recommended for children in the prevention of pneumonia caused by Pneumocystis jirovecii

Special patient groups

For patients with impaired renal function, the dose can be selected according to the following scheme (adults and children over 12 years of age):

It is recommended to measure the plasma concentration of sulfamethoxazole after 2-3 days of treatment (12 hours after taking the drug). If the plasma concentration of sulfamethoxazole reaches 150 μg/ml, treatment should be suspended until the concentration of sulfamethoxazole decreases to 120 μg/ml.

Patients undergoing regular hemodialysis should receive 50% of the usual dose of the drug before hemodialysis and half of the dose after the end of this procedure. Hemodialysis lasts 4 hours, during which 44% of trimethoprim and 57% of sulfamethoxazole are removed from the body. The drug is not recommended for use on days when hemodialysis is not performed.

Biseptol® should be used with particular caution in elderly patients, as this category of patients is more likely to develop adverse reactions, especially in individuals with renal or hepatic insufficiency or with concomitant use of other medications.

Children

The drug in tablet form is used to treat children aged 6 years and older. Children under 6 years of age may use other dosage forms of the drug (suspension) if necessary.

Overdose

It is not known what dose of Biseptol® can be life-threatening. In case of overdose of sulfonamides, there is a lack of appetite, colic-like pain, nausea, vomiting, diarrhea, dizziness, headache, drowsiness, loss of consciousness. Fever, hematuria and crystalluria may occur, in case of chronic overdose, bone marrow suppression and hepatitis may develop.

Acute overdose of trimethoprim may cause nausea, vomiting, dizziness, headache, mental depression, confusion, and bone marrow suppression.

If symptoms of overdose appear, it is necessary to stop using the drug, induce vomiting, and drink plenty of fluids if diuresis is insufficient and kidney function is normal. Acidification of urine will accelerate the excretion of trimethoprim, but may increase the risk of sulfonamide crystallization in the kidneys. The patient's blood count, serum electrolytes, and other biochemical parameters should be monitored. If bone marrow damage or symptoms of hepatitis occur, typical treatment in such cases should be used. Hemodialysis is ineffective. Peritoneal dialysis is ineffective.

In chronic poisoning, spinal cord function is depressed, manifesting as thrombocytopenia, leukopenia, or megaloblastic anemia. In this case, leucovorin (5–15 mg/day) should be administered.

Adverse reactions

In most cases, adequate data to estimate the frequency of adverse reactions were not available. Furthermore, the frequency of occurrence depends on the nosology for which the drug is prescribed.

Adverse reactions with a frequency ranging from "very common" to "rare" are reported in published large clinical trials. Very rare adverse reactions were observed primarily during post-marketing surveillance.

The following scale is used to classify adverse reactions according to their frequency of occurrence: very common ≥ 1/10, common ≥ 1/100 and < 1/10, uncommon ≥ 1/1000 and < 1/100, rare ≥ 1/10,000 and < 1/1000, very rare < 1/10,000, frequency unknown - it is impossible to estimate the frequency based on the available data.

Life-threatening symptoms may rarely occur: Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), acute liver necrosis.

Fungal infections, such as candidiasis, may occur during treatment with the drug.

In addition, among the undesirable effects are:

Infections and infestations: common: fungal infections, very rare: pseudomembranous colitis.

From the blood and lymphatic system: very rarely: hemolytic or aplastic anemia, megaloblastic anemia, eosinophilia, methemoglobinemia, leukopenia, neutropenia and thrombocytopenia, agranulocytosis, pancytopenia or purpura, hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, hypoprothrombinemia.

Immune system disorders: very rare: allergic myocarditis, chills, photophobia, anaphylactic reactions (including severe, life-threatening), allergic vasculitis resembling Henoch-Schönlein purpura, angioedema, allergic skin reaction, general skin reactions, exfoliative dermatitis, rash, serum sickness, periarteritis nodosa, systemic lupus erythematosus.

Respiratory hypersensitivity symptoms, conjunctival and sclera hyperemia. Hypersensitivity reactions with severe course of treatment of pneumocystis pneumonia, rash, pyrexia, neutropenia, thrombocytopenia, increased liver enzymes, hyperkalemia, hyponatremia, rhabdomyolysis.

On the part of the digestive tract: often: diarrhea, nausea (with or without vomiting); infrequently: vomiting; very rarely: glossitis, stomatitis, pancreatitis; frequency unknown: abdominal pain, lack of appetite, isolated cases of pseudomembranous enterocolitis, pseudodiphtheria inflammation of the intestines, increased bilirubin concentration, serum liver enzyme levels.

Hepatobiliary system: very rare: increased levels of aminotransferases and bilirubin in the blood, cholestatic jaundice, liver necrosis; frequency unknown: hepatitis, bile duct syndrome, fulminant hepatitis.

On the part of the kidneys and urinary tract: increased diuresis, crystalluria, renal failure, interstitial nephritis, nephrotoxic syndrome with oliguria or anuria, increased non-protein nitrogen and creatinine in serum.

Metabolism and metabolic disorders: very common: hyperkalemia; very rare: hyponatremia, decreased appetite, hypoglycemia, metabolic acidosis.

Psychiatric disorders: very rare: depression, hallucinations, acute psychosis, delirium and psychosis in elderly patients, frequency unknown: psychotic disorder.

Nervous system disorders: common: headache, very rare: aseptic meningitis*, convulsions, peripheral neuropathy, ataxia, apathy, dizziness; frequency unknown: nervousness, tinnitus, peripheral neuritis, paresthesia, uveitis.

From the side of the organs of hearing and vestibular apparatus: very rare: vertigo, tinnitus.

On the part of the organs of vision: very rare: uveitis.

On the part of the endocrine system: sulfonamides have a chemical affinity with some antithyroid drugs, diuretics (acetazolamide and thiazide), as well as with oral antidiabetic drugs, which may cause cross-allergy.

Skin and subcutaneous tissue disorders: common: rash; very rare: photosensitivity, angioedema, exfoliative dermatitis, persistent drug eruption, erythema multiforme, Stevens-Johnson syndrome*, toxic epidermal necrolysis*; frequency unknown: urticaria, pruritus, desquamative dermatitis.

Musculoskeletal and connective tissue disorders: very rare: arthralgia, myalgia; frequency unknown: isolated cases of rhabdomyolysis.

Respiratory, thoracic and mediastinal disorders: very rare: dyspnoea*, cough*, pulmonary infiltrates*.

Renal and urinary system: very rare