Sulfadimethoxine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SULFADIMETHOXINE (SULFADIMETHOXINE)

Composition:

Active substance: sulfadimethoxine;

1 tablet contains 500 mg of sulfadimethoxine calculated as 100% dry substance;

Excipients: colloidal anhydrous silicon dioxide, potato starch, gelatin, calcium stearate.

Pharmaceutical form. Tablets.

Basic physicochemical properties: white or white with creamy shade tablets, round-shaped, flat-faced, bevel-edged, with a break line on one side.

Pharmacotherapeutic group. Antimicrobial agents for systemic use.

ATC code J01ED01.

Pharmacological properties.

Pharmacodynamics.

Sulfadimethoxine is a long-acting sulfonamide agent. Its mechanism of action is based on competitive antagonism with para-aminobenzoic acid (PABA) and competitive inhibition of the bacterial enzyme dihydropteroate synthase, which is responsible for incorporating PABA into dihydrofolic acid, the immediate precursor of folic acid. This blocks the synthesis of dihydrofolic acid and reduces the amount of metabolically active tetrahydrofolic acid, a cofactor in the synthesis of purines, thymidine, and DNA.

Bacteria sensitive to sulfadimethoxine are those that synthesize folic acid.

It is effective against gram-positive and gram-negative microorganisms: pneumococci, staphylococci, streptococci, Escherichia coli, Klebsiella pneumoniae (Friedländer's bacillus), and the causative agents of dysentery; it is less active against Proteus species.

It is active against the causative agent of trachoma.

Sulfadimethoxine has no effect on bacterial strains resistant to sulfonamides.

Pharmacokinetics.

After oral administration, sulfadimethoxine is absorbed relatively slowly and can be detected in the blood for up to 120 hours. After a single 1 g dose, maximum plasma concentration is reached within 8–12 hours. Maintenance doses of 0.5–1 g maintain the required therapeutic blood concentration throughout the treatment course.

It binds to plasma proteins by 90–98%. With repeated administration, it accumulates in the blood.

It penetrates well into pleural fluid, where its concentration amounts to 60–90% of the blood level. However, unlike other long-acting sulfonamides, it penetrates the blood-brain barrier only in negligible amounts. It is eliminated via the liver and is observed in high concentrations in bile. Sulfadimethoxine belongs to the group of long-acting sulfonamides, with a half-life of elimination of 41 hours.

The drug is very slowly excreted from the body due to high reabsorption in the renal tubules and extensive plasma protein binding. The acetylated form is not reabsorbed in the kidneys and is excreted from the body (up to 83.3% within 96 hours). In urine, the drug is primarily excreted as glucuronide (75–90%), which dissolves well in acidic environments and does not precipitate.

Clinical characteristics.

Indications.

Infectious-inflammatory diseases caused by microorganisms sensitive to sulfadimethoxine: pneumonia, bronchitis, tonsillitis, otitis, sinusitis, inflammatory diseases of biliary and urinary tracts, dysentery, gonorrhea, chancroid, pyoderma, trachoma, wound infections, meningitis, toxoplasmosis, shigellosis, resistant forms of malaria (in combination with antimalarial agents).

Contraindications.

• History of severe toxic-allergic reactions to sulfonamides (agranulocytosis, hemolytic anemia, drug-induced jaundice, severe dermatitis, hepatitis) or other manifestations of hypersensitivity to sulfadimethoxine or any component of the drug, to other sulfonamides or their derivatives;
• bone marrow suppression;
• renal and/or hepatic insufficiency;
• acute porphyria;
• decompensated chronic heart failure;
• azotemia;
• glucose-6-phosphate dehydrogenase deficiency (risk of hemolysis).

Interaction with other medicinal products and other types of interactions.

Nonsteroidal anti-inflammatory drugs, sulfonylurea derivatives, antithrombotic agents, vitamin K antagonists, general anesthetics (e.g., thiopental): enhanced effects of these drugs.

Folic acid, bactericidal antibiotics (including penicillins, cephalosporins): mutual reduction of efficacy.

Para-aminosalicylic acid (PAS), barbiturates: enhanced activity of sulfadimethoxine.

Methotrexate, phenytoin (diphenylhydantoin): mutual enhancement of toxicity. Concomitant use of methotrexate with sulfonamides is not recommended.

Cyclosporine: possible reduction in plasma concentrations of cyclosporine; increased risk of nephrotoxicity.

Diuretics: increased risk of crystalluria.

Antipsychotic agents: concomitant use with clozapine should be avoided (increased risk of agranulocytosis).

Pyrazolone derivatives, indomethacin, and salicylates: enhanced activity and toxicity of sulfonamides.

Erythromycin, lincomycin, tetracyclines, trimethoprim, pyrimethamine: mutual enhancement of antibacterial activity, broadened spectrum of action. Risk of pancytopenia and megaloblastic anemia with concomitant use of pyrimethamine. Increased risk of crystalluria with methenamine.

Rifampicin, streptomycin, monomycin, kanamycin, gentamicin, oxichinoline derivatives (nitroxoline): antibacterial activity of the drugs is not altered.

Nalidixic acid (negramon), local anesthetics (benzocaine, tetracaine, procaine), para-aminobenzoic acid (PABA) and its derivatives: possible reduction in antibacterial activity of sulfonamides due to antagonistic effects.

Chloramphenicol, nitrofurans: reduced overall effect.

Oral estrogen-containing contraceptives: reduced efficacy. Additional contraceptive measures should be used during treatment and for seven days after completion of therapy.

Diagnostic tests: sulfonamides may cause false-positive Benedict's test results for glucose in urine; may interfere with urinary urobilinogen testing.

The drug should not be administered simultaneously with hexamethylenetetramine (urotropine), antidiabetic agents (sulfonylurea derivatives), phenytoin, neodicumarin, and other indirect anticoagulants.

Special precautions.

Fatal cases associated with the use of sulfonamides have been observed very rarely and have occurred as a result of severe adverse reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other pathological conditions affecting the blood system.

Administration of sulfonamides, including sulfadimethoxine, should be discontinued at the first sign of skin rash or any signs of adverse reactions. In rare cases, more serious reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatonecrosis, and severe blood system disorders may develop following the appearance of skin rash.

Clinical signs such as rash, sore throat, fever, joint pain, pallor, purpura, or jaundice may be early indicators of serious adverse reactions during treatment with sulfonamides, including sulfadimethoxine.

Cough, dyspnea, and pulmonary infiltrates have been reported during sulfonamide therapy as manifestations of hypersensitivity reactions affecting the respiratory tract.

Sulfonamides, including sulfadimethoxine, should not be used for the treatment of infections caused by group A beta-hemolytic streptococci, as they do not eradicate the pathogen and therefore cannot prevent complications such as rheumatic fever and glomerulonephritis.

The risk of developing pseudomembranous colitis, which may range from mild to life-threatening forms, exists with the use of nearly all antibacterial agents, including sulfonamides (due to overgrowth of Clostridium difficile). Therefore, this complication must be considered in patients presenting with diarrhea to determine further management strategy.

Sulfadimethoxine should be administered with caution in patients with impaired renal or hepatic function, chronic heart failure, severe allergic disorders or bronchial asthma, and blood system disorders.

Sulfonamides, including sulfadimethoxine, should be used cautiously in patients with diabetes mellitus, as sulfonamides may affect blood glucose levels.

During treatment with sulfonamides, including sulfadimethoxine, especially prolonged therapy and/or high-dose regimens, regular monitoring of renal function, peripheral blood counts, and blood glucose levels is mandatory.

Patients should consume sufficient fluids to prevent crystalluria and the development of urolithiasis. In case of back pain, with or without hematuria, the possibility of these complications should be considered.

Sulfadimethoxine should be avoided in patients aged 65 years and older due to an increased risk of severe adverse effects.

Exposure to direct sunlight and artificial ultraviolet radiation should be avoided due to the potential for photosensitization reactions associated with sulfonamide use.

Since sulfonamides are bacteriostatic rather than bactericidal agents, a full course of therapy is required to prevent infection recurrence and the development of resistant microbial strains.

During treatment, the prescribed dosing regimen must be strictly followed, with the recommended dose administered at 24-hour intervals, without missing doses. If a dose is missed, the next dose should not be doubled.

Use during pregnancy or breastfeeding.

The drug is contraindicated during pregnancy and breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

There is no available information on the effect of the drug on the ability to drive or operate machinery.

Until the individual patient's response to the drug is established, patients should refrain from driving or operating machinery, considering that adverse nervous system reactions such as dizziness, seizures, ataxia, somnolence, depression, and psychosis may occur during sulfadimethoxine therapy.

Dosage and Administration

Sulfadimethoxine should be taken orally after meals, once daily with a 24-hour interval. The duration of treatment depends on the severity of the disease and ranges from 7 to 14 days. After normalization of body temperature, the drug should still be continued at maintenance doses for another 2–3 days.

Adults: On the first day of treatment, administer 1 g (2 tablets); on subsequent days, 500 mg (1 tablet) daily. In severe cases, the dose may be increased to 2 g daily on the first day and up to 1 g daily thereafter.

Children aged 12 years and older: Initial dose is 1 g (2 tablets) on the first day, followed by a maintenance dose of 500 mg (1 tablet) daily.

Children aged 3 to 12 years: On the first day, administer 25 mg/kg body weight; on subsequent days, 12.5 mg/kg body weight daily.

Children

The drug is indicated for children aged 3 years and older.

Overdose

Symptoms: Thirst, dry mouth, anorexia, pain in the right hypochondrium and lumbar region, spasmodic abdominal pain, cholestasis, nausea, vomiting, diarrhea, dermatitis, tachycardia, paresthesia, dizziness, headache, drowsiness, loss of consciousness, oliguria, change in urine color (intense yellow-brown). Hyperthermia, hematuria, and crystalluria may occur. Biochemical blood analysis may reveal increased activity of liver enzymes (ALT, AST, alkaline phosphatase). Pathological blood changes (leukopenia, agranulocytosis, hemolytic anemia) and jaundice are later manifestations of overdose. Methemoglobinemia may develop.

Treatment: Immediate discontinuation of the drug. If necessary, induce vomiting, perform gastric lavage, administer activated charcoal, and give a cleansing enema. Increased fluid intake with alkalizing solutions is recommended. In case of reduced diuresis with normal kidney function, intravenous infusion of fluids is indicated. Subsequent treatment is symptomatic.

In confirmed cases of methemoglobinemia, intravenous administration of 1% methylene blue is indicated.

In severe cases – forced diuresis. Peritoneal dialysis is ineffective; hemodialysis is only moderately effective in treating sulfonamide overdose.

Adverse reactions.

The following adverse reactions may occur, similar to those observed with other sulfonamides.

Gastrointestinal system: Thirst, dry mouth, abdominal pain, dyspeptic symptoms including nausea, vomiting, flatulence, diarrhea, anorexia; stomatitis, sialadenitis, pancreatitis, gastrointestinal bleeding, pseudomembranous colitis.

Hepatobiliary system: Increased blood levels of liver transaminases (ALT, AST, alkaline phosphatase), right upper quadrant pain, hepatomegaly, jaundice, hepatitis, including cholestatic hepatitis, and possible hepatic necrosis.

Nervous system: Headache, neurological reactions including aseptic meningitis, ataxia, mild benign intracranial hypertension, seizures, dizziness, vertigo, somnolence/insomnia, fatigue, peripheral or optic neuropathies.

Psychiatric disorders: Depression, psychosis, hallucinations.

Immune system, skin and subcutaneous tissue: Allergic reactions, including pruritus, skin rashes (including urticaria), allergic dermatitis, drug fever, photosensitization, exfoliative dermatitis, toxic epidermal necrolysis (Lyell's syndrome), nodular erythema, erythema multiforme, erythroderma, fixed drug eruption, Stevens-Johnson syndrome, serum sickness-like syndrome, anaphylactic reactions, periorbital edema, angioneurotic edema, including of the tongue and upper lip, swallowing difficulties. In addition, cases of allergic myocarditis, polyarteritis nodosa, and systemic lupus erythematosus have been reported.

Blood and lymphatic system: Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, eosinophilia, hypoprothrombinemia, risk of acute hemolysis/hemolytic anemia in glucose-6-phosphate dehydrogenase deficiency, purpura, methemoglobinemia.

Urinary system: Change in urine color (intense yellow-brown), crystalluria (possibly associated with flank pain, hematuria, oliguria, anuria); risk can be reduced by taking the drug with sufficient fluid intake and by alkalinizing the urine; possible nephrotoxic reactions: interstitial nephritis, tubular necrosis, renal failure. Increased serum levels of urea and creatinine.

Endocrine system: Hypothyroidism, hypoglycemia.

Respiratory system: Cough, sore throat, dyspnea, pulmonary eosinophilic infiltrates, fibrosing alveolitis.

Other: Tinnitus, tachycardia, arteritis, vasculitis, joint pain, muscle pain.

If adverse reactions occur, the drug should be discontinued immediately.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is an important procedure. It allows continued monitoring of the benefit-risk balance for the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national pharmacovigilance system.

Shelf life. 5 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister pack.

Prescription status. Prescription only.

Manufacturer.

LLC "Agrofarm".

Manufacturer's address and place of business.

113-A, Central Street, Irpin, Kyiv region, 08200, Ukraine.