Sulfasalazine-EN enteric-coated tablets 500 mg No. 50

Instructions for use Sulfasalazine-EN enteric-coated tablets 500 mg No. 50

Composition

active ingredient: sulfasalazine;

1 tablet contains 500 mg of sulfasalazine;

Excipients: povidone, pregelatinized starch, magnesium stearate, colloidal anhydrous silica, titanium dioxide (E 171), yellow iron oxide (E 172), talc, triethyl citrate, macrogol 6000, sodium carboxymethylcellulose, methacrylate copolymer (type A).

Dosage form

Enteric-coated tablets.

Main physicochemical properties: round, light brown, slightly biconvex tablets, film-coated.

Pharmacotherapeutic group

Anti-inflammatory drugs used in intestinal diseases. Aminosalicylic acid and similar drugs. Sulfasalazine. ATX code A07E C01.

Pharmacological properties

Pharmacodynamics

It accumulates in the intestinal connective tissue with the release of 5-aminosalicylic acid, which has anti-inflammatory properties, and sulfapyridine, which has an antimicrobial effect on diplococci, streptococci, gonococci, Escherichia coli. It has an immunosuppressive effect, especially in the connective tissue, intestinal wall and serous fluid, where its concentration is highest. Sulfapyridine reduces systemic inflammation and has an antibacterial effect, inhibits the action of natural killer cells and leukocyte transformation. The anti-inflammatory effect of 5-aminosalicylic acid (mesalazine) is most significant in the treatment of inflammatory bowel diseases. It mainly locally inhibits cyclooxygenase and lipoxygenase in the intestinal wall and thus prevents the formation of prostaglandins, leukotrienes and other inflammatory mediators. Due to low absorption, it reduces inflammation in the large intestine.

Pharmacokinetics

Approximately 30% of an ingested dose of sulfasalazine is absorbed in the small intestine; the remaining 70% is metabolized by intestinal bacteria in the large intestine to sulfapyridine and 5-aminosalicylic acid. Peak serum concentrations of sulfasalazine and its metabolites vary considerably between patients; they are much higher in patients with low levels of acetylation and are associated with a higher incidence of adverse events. Peak serum concentrations of sulfasalazine are reached 3 to 12 hours after administration of enteric-coated tablets. It is highly bound to plasma proteins and connective tissue. Most of the absorbed sulfasalazine is reabsorbed into the intestine with bile; a small amount is excreted unchanged in the urine. The elimination half-life of sulfasalazine is 5 to 10 hours.

The largest part of the released sulfapyridine is absorbed and reaches a maximum concentration in the blood serum 12-24 hours after taking the drug. Metabolized in the liver (by acetylation, hydroxylation and conjugation with glucuronic acid), excreted by the kidneys. The half-life is from 6 to 14 hours, depending on the rate of acetylation. Only about 30% of 5-aminosalicylic acid is absorbed and acetylated in the liver and excreted through the kidneys in the urine. The rest is excreted unchanged in the feces.

Indication

Treatment of mild to moderate ulcerative colitis and as adjunctive therapy in severe ulcerative colitis; prolongation of remission between acute attacks of ulcerative colitis; treatment of patients with rheumatoid arthritis in whom salicylates or other non-steroidal anti-inflammatory drugs (NSAIDs) have not been sufficiently effective (e.g. insufficient therapeutic efficacy or intolerance to appropriate doses of one or more NSAIDs); treatment of juvenile rheumatoid arthritis with polyarthritic syndrome in cases where salicylates or other NSAIDs have not been sufficiently effective.

Contraindication

Hypersensitivity to sulfasalazine, its metabolites, sulfonamides or salicylates; intestinal obstruction or urinary tract obstruction; porphyria, as sulfonamides have been reported to precipitate in acute attacks; severe renal impairment (glomerular filtration rate < 30 ml/min/1.73 m2) and/or severe hepatic impairment; patients with a history of severe asthma attacks, urticaria, rhinitis or other allergic reactions to acetylsalicylic acid or other NSAIDs. Fatal anaphylactic reactions have been reported in such patients.

Interaction with other medicinal products and other types of interactions

There has been a decrease in the absorption of folic acid and digoxin when they are used concomitantly with sulfasalazine.

Bone marrow suppression and leukemia have been reported with concomitant use of the thiopurine 6-mercaptopurine or its prodrug, azathiopurine, with sulfasalazine (oral administration).

Daily doses of sulfasalazine 2 g (maximum 3 g) and weekly doses of methotrexate 7.5 mg (maximum 15 mg) were administered as monotherapy or in combination in 310 patients with rheumatoid arthritis in two controlled 52-week clinical trials. The overall toxicity profile of this combination showed an increased incidence of gastrointestinal adverse events, particularly nausea, compared with the incidence observed with the use of these drugs alone.

Laboratory Tests: There have been several reports of possible interference with laboratory test results (liquid chromatography) by urinary normetanephrine, resulting in false-positive results in patients taking sulfasalazine or its metabolite, mesalamine/mesalazine.

Application features

Sulfasalazine-EN is particularly indicated in patients with ulcerative colitis who cannot take uncoated sulfasalazine tablets due to gastrointestinal intolerance and who have evidence that this intolerance is not primarily due to high blood levels of sulfapyridine and its metabolites, such as in patients who experience nausea and vomiting with the first few doses of the drug or in patients in whom dose reduction has not reduced gastrointestinal side effects. Patients with rheumatoid arthritis or juvenile rheumatoid arthritis should continue to maintain a regimen of rest and physical therapy as indicated. Unlike anti-inflammatory drugs, the effect of Sulfasalazine-EN is not immediately apparent. Concomitant treatment with analgesics and/or nonsteroidal anti-inflammatory drugs is recommended at least until the drug has taken effect.

Liver failure and serum enzyme elevations have been reported during treatment with 5-aminosalicylic acid/mesalazine derivatives in patients with a history of liver disease. Therefore, Sulfasalazine-EN is contraindicated in patients with severe liver disease (see Contraindications). Caution should be exercised when using the drug in patients with mild to moderate liver disease and the drug should be used only if the benefit of use significantly outweighs the risk to the patient. Liver function should be monitored before starting therapy and periodically during treatment. Reports of renal injury, including minimal change nephropathy and chronic interstitial nephritis, have been associated with the use of mesalamine and its prodrugs. Sulfasalazine-EN is contraindicated in patients with severe renal disease (see Contraindications). Caution should be exercised when using the drug in patients with mild to moderate renal impairment and the drug should be used only if the benefit of use significantly outweighs the risk to the patient. Renal function should be monitored before starting therapy and periodically during treatment. Fatal cases due to hypersensitivity reactions, agranulocytosis, aplastic anemia, other blood dyscrasias, liver and kidney damage, irreversible neuromuscular and central nervous system changes, and fibrosing alveolitis have been reported in association with the use of sulfasalazine. The presence of clinical symptoms such as sore throat, fever, pallor, purpura, or jaundice may be signs of serious blood disorders or hepatotoxicity. Patients receiving Sulfasalazine-EN should have a complete blood count and urinalysis with careful microscopic examination. Sulfasalazine treatment should be discontinued while awaiting the results of blood tests.

Oligospermia and infertility may occur in men treated with sulfasalazine. These effects are reversible upon discontinuation of the drug.
within 2-3 months.

Serious infections, including fatal sepsis and pneumonia, have been reported. Some infections have been associated with agranulocytosis, neutropenia, or myelosuppression. If a patient develops a serious infection, the drug should be discontinued. Patients should be closely monitored for signs and symptoms of infection during and after treatment with the drug. A patient who develops a new infection while on treatment with the drug should undergo prompt and complete diagnostic workup to rule out infection and myelosuppression. Caution should be exercised when considering the use of sulfasalazine in patients with a history of recurrent or chronic infections or with comorbidities or concomitant medications that may predispose the patient to infections.

Serious skin reactions, some fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported with sulfasalazine. Patients are at highest risk of developing these events early in therapy, and most of these events occur within the first month of treatment.

Sulfasalazine should be discontinued at the first appearance of skin rash, mucosal lesions, or other signs of hypersensitivity.

Severe, life-threatening systemic hypersensitivity reactions, such as drug eruptions with eosinophilia and systemic symptoms, have been reported in patients receiving sulfasalazine. Even in the absence of rash, early signs of hypersensitivity, such as fever or lymphadenopathy, may occur. If such signs or symptoms are present, the patient should be evaluated promptly. If another cause for these signs or symptoms cannot be identified, sulfasalazine should be discontinued.

Patients with hypersensitivity to furosemide, thiazide diuretics, carbonic anhydrase inhibitors should be monitored for signs of skin rash, mucosal lesions, or other manifestations of allergic reactions.

Precautions.

General. The drug should be prescribed with caution to patients with severe allergies or bronchial asthma. To prevent crystalluria and stone formation, it is necessary to ensure that a sufficient amount of fluid enters the body. Patients with glucose-6-phosphate dehydrogenase deficiency should be carefully observed for signs of hemolytic anemia. This reaction is usually dose-dependent. If toxic reactions or hypersensitivity reactions occur, treatment with the drug should be discontinued immediately.

There have been isolated reports of Sulfasalazine-EN tablets not disintegrating during ingestion. In such cases, the drug should be discontinued immediately.

Information for patients.

Patients should be informed of the possibility of side effects and the need for close medical supervision. The appearance of a sore throat, fever, pallor, purpura, or jaundice may indicate a serious blood disorder. If any of these reactions occur, the patient should seek medical attention.

Patients should be instructed to take the drug in two equal doses, preferably after meals, and to swallow the tablets whole. They should be advised that sulfasalazine may cause urine or skin to turn orange-yellow.

Ulcerative colitis: Patients with ulcerative colitis should be aware that ulcerative colitis is rarely completely cured, and the risk of exacerbations may be significantly reduced after long-term use of Sulfasalazine-EN at a maintenance dose.

Rheumatoid arthritis. Rheumatoid arthritis rarely resolves completely. Therefore, long-term use of the drug is indicated. Patients who require sulfasalazine should be monitored by their physicians to determine the need for long-term use of the drug.

Laboratory tests. Before starting Sulfasalazine-EN, complete blood count with differential and liver function tests should be performed every two weeks for the first three months of therapy. During the next three months, the same tests should be performed once a month, and then every three months and as clinically indicated. Also, periodically during treatment with Sulfasalazine-EN, complete urine analysis and assessment of renal function should be performed.

It may be advisable to measure serum sulfapyridine levels, as concentrations above 50 μg/mL are likely to be associated with an increased incidence of adverse reactions.

Oral sulfasalazine inhibits the absorption and metabolism of folic acid, which may lead to its deficiency in the body (see section "Use during pregnancy or breastfeeding") and, in turn, potentially affect the development of serious blood disorders (such as macrocytosis and pancytopenia).

Ability to influence reaction speed when driving vehicles or other mechanisms

The effect of sulfasalazine on the speed of reactions when driving or using other mechanisms has not been systematically evaluated.

Use during pregnancy or breastfeeding

Published data on the use of sulfasalazine in pregnant women do not indicate a risk of teratogenic effects. The likelihood of adverse effects on the fetus when sulfasalazine is used during pregnancy is low. When administered orally, sulfasalazine inhibits the absorption and metabolism of folic acid and may lead to folic acid deficiency. Since harmful effects cannot be completely excluded, sulfasalazine should be prescribed to pregnant women only if clearly needed and in minimal doses.

Breastfeeding should be discontinued during treatment.

Method of administration and doses

The dose should be selected individually, taking into account the severity of the disease and tolerability of the drug.

If the patient misses a dose, it should be taken as soon as possible. If it is almost time for the next dose, the recommended treatment schedule should be continued (without doubling the dose).

Ulcerative colitis

Initial therapy

Adults: 3-4 g per day in equally divided doses at intervals of no more than 8 hours. It may be advisable to start therapy with lower doses, e.g. 1-2 g per day, to reduce possible gastrointestinal intolerance. If a daily dose of more than 4 g is required to achieve the desired therapeutic effect, the increased risk of toxic reactions should be considered.

Children aged 6 years and over: 40-60 mg/kg body weight during each 24-hour period, divided into 3-6 doses. The drug is not recommended for children for whom a single dose, calculated based on their body weight, is less than 1 tablet (500 mg).

Supportive therapy

Adults: 2 g per day.

Children aged 6 years and over: 30 mg/kg body weight in each 24-hour period, divided into 4 doses. The drug is not recommended for children for whom a single dose calculated based on their body weight is less than 1 tablet (500 mg).

The efficacy of Sulfasalazine-EN in acute ulcerative colitis can be assessed by clinical criteria, including the presence of fever, weight gain, and the extent and frequency of diarrhea and bleeding, as well as by sigmoidoscopy and biopsy specimens. It is often necessary to continue taking the drug even if clinical symptoms, including diarrhea, have been controlled. If satisfactory improvement is confirmed by endoscopic examination, the dose of Sulfasalazine-EN should be reduced to the maintenance dose. If diarrhea recurs, the dose should be increased to the previous effective dose.

Sulfasalazine-EN is particularly indicated for patients who cannot take uncoated sulfasalazine tablets due to gastrointestinal intolerance (e.g. decreased appetite, nausea). If symptoms of gastric intolerance (decreased appetite, nausea, vomiting, etc.) occur with the first few doses of Sulfasalazine-EN, they are likely due to increased total serum sulfapyridine levels and may be reduced by halving the daily dose of Sulfasalazine-EN followed by gradual increases over several days. If gastric intolerance persists, the drug should be discontinued for 5-7 days and then restarted at a lower daily dose.

Rheumatoid arthritis in adults

2 g per day in two equal doses. It is recommended to start therapy with lower doses of Sulfasalazine-EN, for example 0.5-1 g per day to reduce possible gastrointestinal intolerance. The recommended dosage regimen is given below.

In rheumatoid arthritis, the effect of Sulfasalazine-EN can be assessed by the degree of improvement in the condition, the number of joints with active inflammation and its severity. Therapeutic efficacy is observed as early as 4 weeks after the start of treatment with the drug, but some patients may need treatment for 12 weeks before clinical benefit is observed. An increase in the daily dose of the drug to 3 g may be considered if clinical efficacy after 12 weeks is insufficient. Close monitoring of the patient is recommended when using doses above 2 g per day.

Recommended dosage regimen for rheumatoid arthritis in adults:

Juvenile rheumatoid arthritis with polyarthritic syndrome

The drug is not recommended for children for whom the single dose calculated based on their body weight is less than 1 tablet (500 mg).

Children over 6 years of age: 30-50 mg/kg body weight per day, divided into 2 doses. The maximum dose is usually 2 g per day. To reduce possible gastrointestinal intolerance, start with a quarter or third of the planned maintenance dose and increase it every week until the maintenance dose is reached after 1 month.

Individual patients may be sensitive to sulfasalazine treatment. Various desensitization regimens have been reported to be effective in 34 of 53 patients, 7 of 8 patients, and 19 of 20 patients. These regimens involve starting with an initial total daily dose of 50 to 250 mg of sulfasalazine, doubling the dose every 4 to 7 days until the desired therapeutic level is achieved. If symptoms of sensitivity occur, treatment with the drug should be discontinued. Desensitization should not be performed in patients with a history of agranulocytosis or in patients who have had an anaphylactoid reaction to previous sulfasalazine administration.

Children

The safety and efficacy of the drug in the treatment of signs and symptoms of juvenile rheumatoid arthritis with polyarthritic syndrome in patients aged 6 to 16 years have been confirmed by data from appropriate well-controlled studies in adult patients with rheumatoid arthritis. Extrapolation of data from adult patients with rheumatoid arthritis to children with juvenile rheumatoid arthritis with polyarthritic syndrome is based on the similarity of the disease and the effectiveness of therapy in these two groups of patients. Published study results support the possibility of extrapolating the safety and efficacy of sulfasalazine in juvenile rheumatoid arthritis with polyarthritic syndrome (see section "Adverse reactions").

A high incidence of adverse events has been reported in patients with systemic juvenile rheumatoid arthritis. Serum sickness-like reactions have been reported frequently in children with systemic juvenile rheumatoid arthritis. These reactions have often been severe and have included fever, nausea, vomiting, headache, rash, and abnormal liver function tests. Sulfasalazine is not recommended for systemic juvenile rheumatoid arthritis.

Overdose

There is evidence that the frequency and severity of toxic reactions in overdose are directly related to the total serum concentration of sulfapyridine. Symptoms of overdose may include nausea, vomiting, indigestion and abdominal pain. In more severe cases, central nervous system symptoms may occur, including drowsiness and convulsions. Serum sulfapyridine concentrations can be used to monitor recovery from overdose.

Patients with renal impairment are at increased risk of severe toxicity.

There are no documented reports of fatalities from large single doses of sulfasalazine. It is not possible to determine the LD50 in laboratory animals, particularly mice, because the highest oral daily dose of sulfasalazine that can be administered (12 g/kg) was not fatal. Regular use of sulfasalazine at a dose of 16 g per day in tablet form has not resulted in fatalities in patients.

Instructions for overdose. If indicated, gastric lavage or induce vomiting and use of laxatives. Alkalinization of urine. With normal renal function, intensive hydration of the body is necessary. In the presence of oliguria, the amount of fluid and saline administered should be limited and appropriate treatment should be carried out. In case of complete blockage of the kidneys by crystals, catheterization of the ureters can be performed. The low molecular weight of sulfasalazine and its metabolites may facilitate their removal by dialysis.

Patients should be monitored for signs of methemoglobinemia or sulfhemoglobinemia and treated appropriately.

Adverse reactions

The most common adverse reactions associated with the use of sulfasalazine in ulcerative colitis were decreased appetite, headache, nausea, vomiting, stomach upset, and reversible oligospermia. These reactions occurred in approximately one-third of patients. Adverse reactions such as pruritus, urticaria, rash, fever, Heinz body anemia, hemolytic anemia, and cyanosis occurred less frequently (1 in 30 patients or less). Experience shows that the incidence of adverse reactions tends to increase with daily doses of 4 g or more or with total serum sulfapyridine levels above 50 μg/mL.

Sulfasalazine has been associated with similar adverse reactions in adults with rheumatoid arthritis, although the incidence of individual reactions was higher. The following adverse reactions were commonly reported in rheumatoid arthritis studies: nausea (19%), dyspepsia (13%), rash (13%), headache (9%), abdominal pain (8%), vomiting (8%), fever (5%), dizziness (4%), stomatitis (4%), pruritus (4%), liver function test abnormalities (4%), leukopenia (3%), and thrombocytopenia (1%). There was one report of a 10% immunoglobulin suppression. This reaction was slowly reversible and was rarely associated with clinical symptoms.

In general, adverse reactions in patients with juvenile rheumatoid arthritis are similar to those seen in adult patients with rheumatoid arthritis, with the exception of a high incidence of serum sickness-like syndrome in systemic juvenile rheumatoid arthritis. In one clinical trial, a 10% rate of immunoglobulin suppression was observed.

Although the list below only includes a small number of adverse reactions reported with this particular drug, the pharmacological similarity of sulfonamides suggests that each of these reactions should be considered when using Sulfasalazine-EN.

Adverse reactions that occur infrequently or rarely

From the blood and lymphatic system: pancytopenia, aplastic anemia, agranulocytosis, megaloblastic (macrocytic) anemia, purpura, hypoprothrombinemia, methemoglobinemia, macrocytosis, congenital neutropenia and myelodysplastic syndrome.

Immune system disorders: erythema multiforme (Stevens-Johnson syndrome), exfoliative dermatitis, epidermal necrolysis (Lyell's syndrome) with corneal damage, drug rash with eosinophilia and systemic symptoms (DRESS), anaphylaxis, serum sickness syndrome, interstitial lung disease, pneumonitis with or without eosinophilia, vasculitis, fibrosing alveolitis, pleurisy, pericarditis with or without tamponade, allergic myocarditis, polyarteritis nodosa, lupus-like syndrome, hepatitis and hepatic necrosis with or without immune complexes, fulminant hepatitis, sometimes leading to liver transplantation, acute pox-like parapsoriasis (Mucha-Habermann syndrome), rhabdomyolysis, photosensitization, arthralgia, periorbital edema, conjunctival and sclera injection and alopecia, reactions hypersensitivity.

Gastrointestinal: hepatitis, liver failure, pancreatitis, bloody diarrhea, impaired folic acid absorption, impaired digoxin absorption, stomatitis, diarrhea, abdominal pain and neutropenic enterocolitis, exacerbation of ulcerative colitis.

Mental disorders: depression.

Central nervous system: taste disorders, transverse myelitis, convulsions, meningitis, transverse lesion of the posterior spinal cord, cauda equina syndrome, Guillain-Barré syndrome, encephalopathy, peripheral neuropathy, depression of mental functions, dizziness, hearing loss, olfactory disorders, insomnia, ataxia, hallucinations, tinnitus and drowsiness.

Renal: toxic nephropathy with oliguria and anuria, nephritis, nephrotic syndrome, urinary tract infections, hematuria, crystalluria, proteinuria and hemolytic-uremic syndrome, interstitial nephritis.

Other reactions: urine discoloration and skin discoloration, erythema, alopecia, facial edema.

Sulfonamides have some chemical similarity to some vasopressors, diuretics (acetazolamide and thiazides), and oral hypoglycemic drugs. Patients receiving sulfonamides rarely experience goiter enlargement, hypoglycemia, and diuresis.

Cross-sensitivity may occur with these agents. Rats appear to be particularly sensitive to the stromogenic effects of sulfonamides, and long-term use of these agents in this species has resulted in malignant thyroid tumors.

Post-registration notifications

The following are events that have been identified during post-marketing clinical use of products containing mesalamine (or metabolized to mesalamine). Because reports were submitted voluntarily from a population of uncertain size, it is not possible to estimate their frequency. These events were included based on a combination of factors such as seriousness, frequency of reporting, or potential causal relationship to mesalamine.

From the side of the blood and lymphatic system: pseudomononucleosis.

Cardiac: myocarditis.

Hepatobiliary: Hepatotoxicity, including elevations in liver function tests (AST/AST, ALT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), jaundice, cholestatic jaundice, cirrhosis, cholestatic hepatitis, cholestasis and possible hepatocellular injury including hepatic necrosis and hepatic failure, has been reported. Some of these cases have been fatal. One case of Kawasaki-like syndrome involving liver function abnormalities has been reported.

Immune system disorders: anaphylaxis.

Metabolism: loss of appetite, folate deficiency.

From the urinary system: nephrolithiasis.

Respiratory, thoracic and mediastinal disorders: cough, dyspnea, oropharyngeal pain.

Skin and subcutaneous tissue disorders: angioedema, purpura, exanthema, toxic pustuloderma, lichen planus, photosensitivity, Gougereau-Sjogren's syndrome.

Vascular disorders: pallor.

Drug abuse and dependence: Not reported.

Laboratory tests: increased liver enzymes, induction of autoantibodies.

Expiration date

5 years.

Storage conditions

Store at a temperature not exceeding 25 °C in the original packaging. Keep out of the reach of children.

Packaging

10 tablets in a blister; 5 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

KRKA, dd, Novo mesto/KRKA, dd, Novo mesto.

Location of the manufacturer and its business address

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.