Bi-tol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BI-TOL (BI-TOL)

Composition:

Active substances: sulfamethoxazole, trimethoprim;

5 ml of oral suspension contain 200 mg of sulfamethoxazole and 40 mg of trimethoprim;

Excipients: confectioner's sugar; sodium saccharin; sodium carboxymethylcellulose; xanthan gum; racemic menthol; methylparahydroxybenzoate (E 218); propylparahydroxybenzoate (E 216); flavoring agent "Tropic 566" (contains 1,2-propylene glycol); citric acid monohydrate; sodium citrate; purified water.

Pharmaceutical form. Oral suspension.

Main physico-chemical properties: white or almost white suspension with a characteristic aromatic odor and sweet taste. Sedimentation may occur upon storage, which disappears upon shaking.

Pharmacotherapeutic group.

Antibacterials for systemic use. Combinations of sulfonamides and trimethoprim, including derivatives. ATC code J01E E01.

Pharmacological properties.

Pharmacodynamics.

The antibacterial activity of Bi-tolu in vitro extends to both Gram-positive and Gram-negative pathogens, including the microorganisms listed below, although sensitivity may vary depending on the geographical region.

Commonly sensitive pathogens (MIC90 ≤ 2 mg/L [trimethoprim]; ≤ 38 mg/L [sulfamethoxazole]).

Cocci: Moraxella catarrhalis.

Gram-negative bacilli: Haemophilus parainfluenzae, Citrobacter freundii, other Citrobacter spp., Klebsiella oxytoca, other Klebsiella spp., Enterobacter cloacae, Enterobacter aerogenes, Hafnia alvei, Serratia marcescens, Serratia liquefaciens, other Serratia spp., Yersinia enterocolitica, other Yersinia spp., Vibrio cholerae.

Various Gram-negative bacilli: Edwardsiella tarda, Alcaligenes faecalis, Burkholderia pseudomallei.

Based on clinical experience, the following pathogens are also considered sensitive: Brucella, Listeria monocytogenes, Nocardia asteroides, Pneumocystis carinii, Cyclospora cayetanensis.

Intermediately sensitive pathogens (MIC90 = 4 mg/L [trimethoprim]; = 76 mg/L [sulfamethoxazole]).

Cocci: Staphylococcus aureus (methicillin-sensitive and methicillin-resistant), Staphylococcus spp. (coagulase-negative), Streptococcus pneumoniae (penicillin-sensitive, penicillin-resistant).

Gram-negative bacilli: Haemophilus influenzae (β-lactamase-positive, β-lactamase-negative), Haemophilus ducreyi, E. coli, Klebsiella pneumoniae, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, other Providencia spp., Salmonella typhi, Salmonella enteritidis, Stenotrophomonas maltophilia (formerly Xanthomonas maltophilia).

Various Gram-negative bacilli: Acinetobacter lwoffi, Acinetobacter anitratus (particularly A. baumannii), Aeromonas hydrophila.

Resistant pathogens (MIC90 ≥ 8 mg/L [trimethoprim]; ≥ 152 mg/L [sulfamethoxazole]).

Burkholderia (Pseudomonas) cepacia, Pseudomonas aeruginosa, Mycoplasma spp., Mycobacterium tuberculosis, Shigella spp., Treponema pallidum, Neisseria gonorrhoeae, Bacteroides, and other strictly anaerobic pathogens.

When using Bi-tolu empirically, consideration must be given to the local prevalence of resistance to the active substances among bacteria causing the infection being treated.

In infections caused by moderately sensitive pathogens, susceptibility testing should be performed to rule out resistance.

Susceptibility to the active substances can be determined using standard methods such as disk diffusion or dilution methods recommended by the Clinical and Laboratory Standards Institute (CLSI). CLSI recommends using the following susceptibility criteria:

Disk: 1.25 mcg trimethoprim and 23.75 mcg sulfamethoxazole.

** Trimethoprim (TMP) and sulfamethoxazole (SMX) in a ratio of 1 to 19.

Development of resistance, cross-resistance.

Resistance to Biseptol during treatment develops only rarely. Cross-resistance exists among all sulfonamides; cross-resistance to chemically unrelated antibiotics does not develop as a result of acquired resistance to Biseptol.

Synergism, antagonism.

A pronounced synergism is observed between sulfamethoxazole and trimethoprim. This synergism is evident in most cases even in the presence of resistance to one of the two components of the drug.

Pharmacokinetics.

With regard to clinically significant pharmacokinetic properties, trimethoprim and sulfamethoxazole are largely similar.

Absorption.

After oral administration, trimethoprim and sulfamethoxazole are rapidly and almost completely absorbed (bioavailability 80–100%) in the upper gastrointestinal tract. After a single dose of 160 mg trimethoprim + 800 mg sulfamethoxazole, maximum plasma concentrations of 1.5–3 mg/L for trimethoprim and 40–80 mg/L for sulfamethoxazole are reached within 1–4 hours. If dosing is repeated every 12 hours, the steady-state plasma concentrations of sulfamethoxazole and trimethoprim are typically 50–100% higher than after a single oral dose. Plasma levels are proportional to the dose. The effect of food on the kinetics of Biseptol's active substances has not been studied. However, if trimethoprim suspension is taken after food, absorption is lower than when taken on an empty stomach, although the rate of absorption under the influence of a normal meal is not altered.

Distribution.

The volume of distribution of trimethoprim and sulfamethoxazole is approximately 1.2–1.5 L/kg and 0.15–0.36 L/kg, respectively.

At the aforementioned concentrations, 42–46% of trimethoprim and 66% of sulfamethoxazole are bound to plasma proteins.

Studies in animals and humans have shown that Biseptol penetrates well into tissues. A significant amount of trimethoprim and a small amount of sulfamethoxazole pass from the bloodstream into interstitial fluid and other extravascular body fluids. Concentrations of trimethoprim and sulfamethoxazole may be elevated in inflamed tissues.

Trimethoprim and sulfamethoxazole have been detected in the fetal placenta, umbilical cord blood, amniotic fluid, and fetal tissues (liver, lungs), confirming penetration of these substances through the placental barrier. Typically, trimethoprim concentrations are close to maternal blood levels, whereas fetal sulfamethoxazole levels are lower.

Both substances penetrate into breast milk. Concentrations in breast milk are similar (trimethoprim) or lower (sulfamethoxazole) compared to maternal plasma concentrations.

Metabolism.

Approximately 50–70% of the trimethoprim dose and 10–30% of sulfamethoxazole are excreted in urine unchanged. The main metabolites of trimethoprim are the 1- and 3-oxides and 3’- and 4’-hydroxy derivatives; some of these metabolites are active. Sulfamethoxazole is metabolized in the liver primarily via N4-acetylation and to a lesser extent via glucuronidation; its metabolites are inactive.

Elimination.

Under conditions of normal renal function, the elimination half-lives of both components are very similar (on average 10 hours for trimethoprim and 11 hours for sulfamethoxazole).

Total clearance is approximately 100 mL/min for trimethoprim and 20 mL/min for sulfamethoxazole.

The elimination half-life of trimethoprim in children is approximately half that in adults, whereas no significant differences are observed with regard to sulfamethoxazole.

Both substances and their metabolites are primarily excreted by the kidneys via glomerular filtration and tubular secretion. Concentrations of trimethoprim and sulfamethoxazole in urine are approximately 100 and 5 times higher, respectively, than corresponding plasma concentrations.

Renal clearance rates are 20–80 mL/min for trimethoprim and 1–5 mL/min for sulfamethoxazole.

Both substances have been detected in feces in insignificant amounts.

Pharmacokinetics in special patient groups.

In elderly patients and in patients with impaired renal function, the elimination half-lives of both drug components are prolonged, necessitating appropriate dose adjustment.

Although the pharmacokinetics, particularly of trimethoprim, do not undergo significant changes in patients with impaired liver function, caution is advised when using Biseptol at high doses in cases of severe hepatic impairment. Monitoring of blood drug levels and dose adjustment are necessary when hemodialysis is performed.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to the active substances, namely:

‒ infections of the upper and lower respiratory tract, ear infections: exacerbations of chronic bronchitis, bronchiectasis, pneumonia (including pneumonia caused by Pneumocystis carinii), sinusitis, otitis media;

‒ urinary and genital tract infections: acute and chronic cystitis, pyelonephritis, urethritis, prostatitis;

‒ gastrointestinal tract infections, including typhoid and paratyphoid fever (including treatment of chronic carriers) and cholera (as an adjunct to fluid and electrolyte replacement);

‒ other bacterial infections caused by sensitive microorganisms: acute brucellosis, nocardiosis, actinomycetoma (except that caused by true fungi), South American blastomycosis (Paracoccidioides brasiliensis).

In osteomyelitis – as a last-line agent (e.g., when vancomycin is contraindicated), if sensitivity of multidrug-resistant pathogens to the active substances has been demonstrated.

Contraindications.

‒ Hypersensitivity to the active substances, sulfonamides, trimethoprim, or to any of the excipients.

‒ Severe parenchymal liver disease.

‒ Severe renal impairment (creatinine clearance < 15 mL/min), if periodic monitoring of plasma concentrations of trimethoprim and sulfamethoxazole is not feasible.

‒ Megaloblastic anemia due to folate deficiency.

‒ Immune thrombocytopenia caused by trimethoprim and/or sulfonamides.

‒ Hematological disorders.

‒ Combination with dofetilide (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Pharmacokinetic interactions

Trimethoprim is an inhibitor of the organic anion transporter 2 (OAT2) and a weak inhibitor of CYP2C8. Sulfamethoxazole is a weak inhibitor of CYP2C9.

Increased digoxin blood levels may occur during concomitant treatment with Bi-tol, particularly in elderly patients.

After administration of Bi-tol at usual doses, an increase in the half-life of phenytoin by 39% and a decrease in metabolic clearance rate by 27% have been observed. Patients receiving phenytoin should be monitored for signs of phenytoin toxicity.

Patients receiving sulfonylurea derivatives (e.g., glibenclamide, glipizide, glimepiride, chlorpropamide, tolbutamide), repaglinide, rosiglitazone, or pioglitazone should be regularly monitored for hypoglycemia.

The efficacy of tricyclic antidepressants may be reduced when used concomitantly with Bi-tol.

Sulfonamides, including sulfamethoxazole, may displace methotrexate from plasma protein binding sites and impair renal methotrexate transport, thereby increasing free methotrexate concentration and enhancing its effects.

Concomitant use of Bi-tol may necessitate dose adjustment of oral antidiabetic agents.

Like other antibiotics, Bi-tol may reduce the effectiveness of oral contraceptives; therefore, patients should be advised to use additional contraceptive measures during treatment with Bi-tol.

Observed interactions

In elderly patients concurrently taking certain diuretics, particularly thiazide-type diuretics, an increased incidence of thrombocytopenia with purpura has been observed. Therefore, platelet levels should be regularly monitored in patients receiving diuretics.

Concomitant use may increase systemic exposure to medicinal products metabolized primarily via CYP2C9, such as coumarins (warfarin, acenocoumarol, phenprocoumon), phenytoin, and sulfonylurea derivatives (e.g., glibenclamide, glipizide, glimepiride, chlorpropamide, tolbutamide).

Coagulation should be monitored in patients receiving coumarins.

In patients receiving the drug and cyclosporine after kidney transplantation, reversible deterioration of renal function has been observed.

Cases of pancytopenia have been reported in patients receiving a combination of trimethoprim and methotrexate (see section "Special precautions for use"). Trimethoprim has low affinity for human dihydrofolate reductase; however, it can potentiate the adverse effects of methotrexate, especially in the presence of other risk factors such as advanced age, hypoalbuminemia, renal impairment, and reduced bone marrow reserve. These adverse reactions may occur particularly with high-dose methotrexate. Patients at risk should be treated with folic acid or calcium folinate to counteract the hematotoxic effects of methotrexate (urgent treatment).

Isolated reports indicate that patients taking pyrimethamine-containing drugs for malaria prophylaxis at doses exceeding 25 mg pyrimethamine per week may develop megaloblastic anemia when Bi-tol is taken concomitantly.

Zidovudine and, to a lesser extent, Bi-tol, both induce hematological disturbances. Therefore, a potentially additive pharmacodynamic effect is possible. Monitoring for hematological toxicity, along with dose adjustment (if necessary), is recommended when this medicinal product is used concomitantly with zidovudine.

Concomitant use of azathioprine or mercaptopurine increases the risk of hematological adverse reactions, particularly in patients receiving long-term treatment and in those at increased risk of folate deficiency. If a patient is receiving azathioprine or mercaptopurine, consideration should be given to prescribing an alternative agent. If Bi-tol is used in combination with azathioprine or mercaptopurine, the patient should be monitored for hematological toxicity.

Due to the potassium-sparing effect of the drug, caution should be exercised when used concomitantly with other medicinal products that increase serum potassium levels, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Frequent monitoring of serum potassium levels is recommended, especially in patients with pre-existing potassium disturbances, renal impairment, or those receiving high doses of the drug.

Concomitant use with Bi-tol may increase systemic exposure to medicinal products transported via OAT2, i.e., dofetilide, amantadine, and memantine.

The drug must not be used in combination with dofetilide (see section "Contraindications").

There is evidence that trimethoprim inhibits renal excretion of dofetilide. When trimethoprim 160 mg in combination with sulfamethoxazole 800 mg twice daily was administered concomitantly with dofetilide 500 mcg twice daily for 4 days, an increase of 103% in the area under the concentration-time curve (AUC) and of 93% in maximum plasma concentration (Cmax) of dofetilide was observed.

Dofetilide may cause QT interval prolongation with serious ventricular arrhythmias, including bidirectional ventricular tachycardia (torsades de pointes), directly related to plasma concentrations of dofetilide.

In patients receiving amantadine or memantine, the risk of neurological adverse reactions such as delirium and myoclonus is increased. Toxic delirium has been reported after concomitant use of Bi-tol and amantadine.

Concomitant use of Bi-tol may increase systemic exposure to medicinal products metabolized primarily by CYP2C8, including paclitaxel, amiodarone, dapsone, repaglinide, rosiglitazone, and pioglitazone.

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

Both dapsone and Bi-tol can cause methemoglobinuria. Patients receiving dapsone in combination with Bi-tol should be monitored for methemoglobinuria. Alternative treatment options should be considered if possible.

Pharmacodynamic interactions with unestablished mechanism

Concomitant use with clozapine, which may cause agranulocytosis, should be avoided.

Special precautions for use.

Bi-Tol should be used with caution in patients with a history of allergy or bronchial asthma.

Depending on the dose and duration of treatment, there may be an increased risk of severe adverse reactions in elderly patients, patients with complicated conditions such as impaired liver and/or kidney function, and patients concurrently taking other medicinal products. Rarely, fatal outcomes have been reported due to adverse reactions, specifically persistent pathological changes in blood cell composition (dyscrasia), Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), drug rash with eosinophilia and systemic symptoms (DRESS), and fulminant liver necrosis.

Except in exceptional cases, the drug should not be prescribed to patients with serious persistent pathological changes in blood cell composition. Occasionally, the drug has been used in patients receiving cytotoxic agents for the treatment of leukemia, without any observed adverse effects on bone marrow or peripheral blood.

Due to the potential for hemolysis, Bi-Tol should not be administered to patients with glucose-6-phosphate dehydrogenase deficiency or certain hemoglobinopathies (Hb-Zurich, Hb-Cologne), except in cases of extreme necessity and only at minimal doses.

Treatment should be discontinued immediately at the first sign of skin rash or any other serious adverse reactions.

To minimize the risk of adverse reactions, the duration of Bi-Tol treatment should be as short as possible, particularly in elderly patients. In cases of impaired renal function, dosage adjustments should be made according to the section "Dosage and administration."

Severe persistent diarrhea during or after treatment may indicate pseudomembranous colitis, which requires urgent treatment. In such cases, Bi-Tol should be discontinued and appropriate diagnostic and therapeutic measures initiated (e.g., oral vancomycin 250 mg four times daily). Antiperistaltic agents are contraindicated in these cases.

If Bi-Tol is taken for a prolonged period, regular complete blood counts should be performed. If a significant reduction in blood cell counts below normal levels occurs, Bi-Tol should be discontinued.

During prolonged treatment, monitoring of renal and urinary tract function is necessary, especially in patients with impaired renal function.

To prevent crystalluria during treatment, adequate fluid intake and diuresis should be maintained.

Since Bi-Tol, like other antibiotics, may reduce the effectiveness of oral contraceptives, patients should be advised to use additional contraceptive measures during treatment.

Prolonged treatment with Bi-Tol may lead to overgrowth of resistant microorganisms and fungi. In case of superinfection, appropriate treatment should be initiated immediately.

Caution is required when treating patients with porphyria or thyroid dysfunction.

In elderly patients or patients with impaired renal function, blood changes indicating folic acid deficiency may occur. These resolve after administration of folic acid.

Caution is required when treating patients with additional risk factors for folic acid deficiency, such as treatment with phenytoin or other folic acid antagonists, or inadequate nutrition.

Cases of pancytopenia have been reported in patients taking a combination of trimethoprim and methotrexate (see section "Interaction with other medicinal products and other forms of interaction").

Trimethoprim has been shown to have an adverse effect on phenylalanine metabolism. However, this does not affect patients with phenylketonuria who are on an appropriate diet.

Individuals who are "slow acetylators" have an increased risk of idiosyncratic reactions to sulfonamides.

If you have an intolerance to certain sugars, consult your doctor before taking this medicinal product.

Respiratory toxicity

Very rare, severe cases of respiratory toxicity have been reported during treatment with sulfamethoxazole/trimethoprim, sometimes progressing to acute respiratory distress syndrome (ARDS). Pulmonary manifestations such as cough, fever, and dyspnea, in combination with radiological signs of pulmonary infiltrates and worsening lung function, may be early signs of ARDS. In such cases, sulfamethoxazole/trimethoprim should be discontinued and appropriate treatment initiated.

Hemophagocytic lymphohistiocytosis

Very rarely, cases of hemophagocytic lymphohistiocytosis have been reported in patients receiving sulfamethoxazole/trimethoprim. Hemophagocytic lymphohistiocytosis is a syndrome of pathological immune activation that is life-threatening and characterized by clinical signs and symptoms of excessive systemic inflammation (such as fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, high serum ferritin levels, cytopenia, and hemophagocytosis). Patients developing early signs of pathological immune activation should be evaluated immediately. If the diagnosis of hemophagocytic lymphohistiocytosis is confirmed, treatment with sulfamethoxazole/trimethoprim should be discontinued.

Use during pregnancy or breastfeeding

Pregnancy

Since trimethoprim and sulfamethoxazole cross the placental barrier and may thus affect folic acid metabolism and potentially cause kernicterus, the drug should not be administered during pregnancy. In animal studies, very high doses of co-trimoxazole caused developmental malformations typical of folic acid antagonists.

Based on studies in pregnant women, scientific literature, and spontaneous reports of birth defects, co-trimoxazole is not considered to pose a significant teratogenic risk in humans.

Breastfeeding

Since trimethoprim and sulfamethoxazole are excreted in breast milk, breastfeeding during treatment with this drug is not recommended.

Ability to influence reaction speed when driving or operating machinery

Bi-Tol generally does not directly affect the ability to drive or operate machinery. However, there is a possibility of nervous system and psychiatric adverse effects that may affect this ability, in some cases significantly (see section "Adverse reactions").

Method of administration and dosage.

Shake before use.

The medication should be administered every 12 hours. It is best to take it after a meal with plenty of fluid. In acute infections, Bi-tol should be prescribed for a period of not less than 5 days.

For children under 12 years of age:

The dosage regimen described for children approximately corresponds to a daily dose of 6 mg of trimethoprim and 30 mg of sulfamethoxazole per 1 kg of body weight. In severe infections, doses for children may be increased by 50%.

Dosing in special cases:

Patients with pneumonia caused by Pneumocystis carinii

The recommended dose is up to 20 mg of trimethoprim and up to 100 mg of sulfamethoxazole per 1 kg of body weight per day, administered orally in equally divided doses every 6 hours for 14 days.

General recommendations for maximum dose based on body weight in patients with pneumonia caused by Pneumocystis carinii:

For prophylaxis of Pneumocystis carinii-induced pneumonia, adults should be given 800 mg of sulfamethoxazole and 160 mg of trimethoprim. For children, the recommended dose is trimethoprim 150 mg/m²/day and sulfamethoxazole 750 mg/m²/day, administered in two divided doses for three consecutive days.

The maximum daily dose should not exceed 320 mg of trimethoprim and 1600 mg of sulfamethoxazole. The table below provides general recommendations for maximum dosage based on body weight for patients with Pneumocystis carinii-induced pneumonia:

Dosage for patients with renal impairment

Patients undergoing hemodialysis

If B-Tol is indicated for patients undergoing hemodialysis, it should be administered initially in the standard dose, followed by half or one-third of the standard dose every 24–48 hours. Monitoring of serum drug concentration and appropriate dose adjustment are required.

Children

The drug can be used in children aged from 2 months to 12 years.

Overdose

Symptoms

Acute overdose: symptoms may include nausea, vomiting, diarrhea, headache, vertigo, dizziness, intellectual and visual disturbances; in severe cases – crystalluria, hematuria, and anuria.

Chronic overdose: suppression of hematopoiesis manifested by thrombocytopenia, leukopenia, and other pathological blood changes due to folic acid deficiency.

Treatment

Depending on symptoms, the following measures should be taken: prevention of further absorption, gastric lavage, administration of emetic agents, enhancement of renal excretion by forced diuresis (alkalinization of urine promotes elimination of sulfamethoxazole), hemodialysis (peritoneal dialysis is ineffective), monitoring of blood analysis and electrolyte levels. Specific treatment should be administered in case of pronounced hematological abnormalities or jaundice. To counteract the effects of trimethoprim on hematopoiesis, calcium folinate may be given intramuscularly at a dose of 3–6 mg for 5–7 days.

Adverse reactions

The main adverse reactions are skin reactions and mild gastrointestinal disturbances, observed during treatment in approximately 5% of cases.

Infections and infestations: fungal infections, particularly candidiasis.

Blood and lymphatic system disorders: leucopenia, granulocytopenia, thrombocytopenia, eosinophilia; agranulocytosis, anaemia (megaloblastic, immune haemolytic, aplastic), methaemoglobinaemia, pancytopenia. Blood-related changes are usually asymptomatic and reversible upon discontinuation of the drug.

Vascular disorders: circulatory shock (frequency – unknown). Cases of circulatory shock, often associated with fever and lack of response to standard hypersensitivity treatment, have been reported during administration of sulfamethoxazole-trimethoprim, primarily in immunocompromised patients.

Immune system disorders: allergic reactions (possibly delayed), including fever, angioedema, urticaria, anaphylactoid reactions and serum sickness, polyarteritis nodosa, allergic myocarditis, exfoliative dermatitis, systemic lupus erythematosus.

Metabolism and nutrition disorders: increased serum potassium levels – in a significant number of patients with Pneumocystis carinii pneumonia, high doses of trimethoprim cause progressive but reversible elevation of serum potassium concentration. In patients with impaired potassium metabolism or renal insufficiency, or in those taking drugs that induce hyperkalaemia, trimethoprim may cause hyperkalaemia (in over 60% of patients), even when used at recommended doses. Careful monitoring of serum potassium levels is required in such patients.

Hyponatraemia.

Hypoglycaemia in non-diabetic patients, usually occurring within the first few days of treatment. Patients at particular risk include those with impaired renal function, hepatic disorders, malnutrition, and those receiving high doses of trimethoprim–sulfamethoxazole.

Psychiatric disorders: hallucinations, depression, apathy, insomnia, increased fatigue. Delirium and psychosis, particularly in elderly patients.

Nervous system disorders: neuropathy (including peripheral neuritis and paraesthesia), uveitis. Aseptic meningitis or meningitis-like symptoms, ataxia, convulsions, vertigo, tinnitus, headache.

Respiratory system disorders: pneumonitis with eosinophilic infiltration, dyspnoea, cough, shallow breathing, pulmonary infiltrates. Cough, shallow breathing, and pulmonary infiltrates may be early signs of respiratory hypersensitivity, which very rarely has been fatal.

Gastrointestinal disorders: nausea (with or without vomiting); anorexia, stomatitis, glossitis, diarrhoea; pseudomembranous enterocolitis, acute pancreatitis in severely ill patients.

Hepatobiliary disorders: elevated transaminase and bilirubin levels, hepatitis, cholestasis, liver necrosis, vanishing bile duct syndrome, fulminant hepatitis.

Skin and subcutaneous tissue disorders: skin rash. These adverse effects are mostly mild and rapidly resolve after discontinuation of the drug.

As with other medicinal products containing sulfonamides, rare adverse reactions include erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), drug reaction with eosinophilia and systemic symptoms (DRESS), purpura, Henoch–Schönlein purpura, photosensitivity.

Musculoskeletal and connective tissue disorders: arthralgia, myalgia, rhabdomyolysis.

Renal and urinary disorders: impaired renal function and renal failure, oliguria, anuria, interstitial nephritis, elevated blood urea nitrogen, elevated serum creatinine, crystalluria. Sulfonamides, including Bi-tol, may enhance diuresis, particularly in patients with oedema due to cardiovascular disorders.

Adverse effects in HIV-infected patients:

HIV-infected patients, who often have multiple comorbidities, usually receive long-term prophylaxis or treatment for Pneumocystis carinii (Pneumocystis jiroveci) pneumonia using high doses of the drug. Apart from a slightly increased number of additional adverse effects, the adverse effect profile in these patients is similar to that in non-HIV-infected populations. However, certain adverse effects occur more frequently (in approximately 65% of patients) and are often more severe, necessitating discontinuation of Bi-tol treatment in 20–25% of patients.

Specifically, the following adverse reactions have been observed with additional or increased frequency:

Blood and lymphatic system disorders: predominantly neutropenia, but also anaemia, leucopenia, granulocytopenia, and thrombocytopenia; agranulocytosis.

Immune system disorders: fever, usually associated with skin rashes; allergic reactions such as angioedema, anaphylactoid reactions, and serum sickness.

Metabolism and nutrition disorders: hyperkalaemia (careful monitoring of serum potassium levels is required); hyponatraemia, hypoglycaemia.

Psychiatric disorders in HIV-infected patients: acute psychosis.

Nervous system disorders: neuropathy (including peripheral neuritis and paraesthesia), hallucinations, uveitis. Aseptic meningitis or meningitis-like symptoms, ataxia, convulsions, resting tremor resembling Parkinson’s disease, sometimes associated with apathy, clonus of the feet, wide-based gait, vertigo, tinnitus.

Respiratory disorders: pneumonitis with eosinophilic infiltration.

Gastrointestinal disorders: anorexia, nausea with or without vomiting, diarrhoea, stomatitis, glossitis, pancreatitis.

Hepatobiliary disorders: elevated liver enzymes/transaminases, cholestatic jaundice; severe hepatitis.

Skin disorders: maculopapular rashes, usually pruritic, which rapidly resolve after discontinuation of the drug, photosensitivity, erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), Henoch–Schönlein purpura.

Musculoskeletal and connective tissue disorders: arthralgia, myalgia, rhabdomyolysis.

Renal and urinary disorders: impaired renal function, azotaemia, elevated serum creatinine, crystalluria; sulfonamides, including Bi-tol, may enhance diuresis, particularly in patients with oedema due to cardiovascular disorders.

Shelf life. 3 years.

After first opening of the container, the product remains suitable for use for 28 days.

Storage conditions.

Store at temperatures not exceeding 25 °C, in a place inaccessible to children.

Packaging.

100 g in a bottle or jar; 1 bottle or jar with a dosing cup in a carton.

Prescription category. Prescription only.

Manufacturer.

LLC "DKP "Pharmaceutical Factory".

Manufacturer's address and place of business.

4 Korolova St., Stanishivka village, Zhytomyr district, Zhytomyr region, 12430, Ukraine.