Salazopyrin en-tabs

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SALAZOPYRIN en-tabs (SALAZOPYRIN en-tabs)

Composition:

Active substance: sulfasalazine;

One tablet contains sulfasalazine 500 mg, equivalent to 535 mg of sulfasalazine with povidone;

Excipients: pregelatinized starch, magnesium stearate, colloidal anhydrous silicon dioxide, cellulose acetate phthalate, propylene glycol, talc, macrogol, carnauba wax, glycerol monostearate, white wax.

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties: yellow-orange, elliptical, convex tablets coated with an enteric coating, marked with the letters "KPh" on one side and the product code "102" on the other.

Pharmacotherapeutic group. Anti-inflammatory agents used in intestinal disorders. Aminosalicylic acid and related agents.

ATC code A07EC01.

Pharmacological properties.

Pharmacodynamics.

The mechanism of action of sulfasalazine and its metabolites, 5-aminosalicylic acid and sulfapyridine, may be related to the anti-inflammatory and/or immunomodulatory properties observed in animals and in vitro studies, its affinity for connective tissue, and/or its relatively high concentration in serous fluids, liver, and intestinal wall, as demonstrated in radiographic studies in animals. Clinical studies in ulcerative colitis, including administration of sulfasalazine, sulfapyridine, and 5-aminosalicylic acid administered rectally, have shown that the main therapeutic effect may be attributed to the 5-aminosalicylic acid molecule. The relative contribution of the parent drug and its major metabolites in rheumatoid arthritis is unknown.

Pharmacokinetics.

In vivo studies have shown that the absolute bioavailability of sulfasalazine after oral administration is less than 15% for the parent drug. In the intestine, sulfasalazine is metabolized by intestinal bacteria into sulfapyridine and 5-aminosalicylic acid. Of these two compounds, sulfapyridine is relatively well absorbed from the intestine and more extensively metabolized, whereas 5-aminosalicylic acid is absorbed much less efficiently.

Absorption. After oral administration of 1 g of sulfasalazine to 9 healthy men, less than 15% of the dose was absorbed as the parent drug.

Detectable serum concentrations of sulfasalazine appeared in healthy subjects within 90 minutes after oral administration. Maximum concentrations of sulfasalazine occur between 3 and 12 hours after oral intake, with a mean peak concentration (6 µg/mL) reached at 6 hours. Concurrently, peak plasma levels of sulfapyridine and 5-aminosalicylic acid occur approximately 10 hours after administration. This longer time to peak concentration indicates that the drug passes through the gastrointestinal tract to the lower intestinal segments, where bacterial metabolism occurs. Sulfapyridine is well absorbed from the colon, with an expected bioavailability of 60%. According to the same study, 5-aminosalicylic acid is absorbed from the gastrointestinal tract much less efficiently, with an expected bioavailability of 10–30%.

Distribution. After intravenous injection, the calculated volume of distribution for sulfasalazine was 7.5 ± 1.6 L. Sulfasalazine is highly bound to albumin (>99.3%), whereas sulfapyridine is bound to albumin by approximately 70%. Acetyl-sulfapyridine, the main metabolite of sulfapyridine, is protein-bound in plasma by approximately 90%.

Metabolism. As noted above, sulfasalazine is metabolized by intestinal bacteria into sulfapyridine and 5-aminosalicylic acid. Approximately 15% of the sulfasalazine dose is absorbed as the parent drug and is partially metabolized in the liver into the same compounds. The reported plasma half-life after intravenous administration of sulfasalazine is 7.6 ± 3.4 hours. The main metabolic pathway of sulfapyridine is acetylation, forming acetyl-sulfapyridine. The rate of sulfapyridine metabolism into acetyl-sulfapyridine depends on the acetylator phenotype. In fast acetylators, the mean plasma half-life of sulfapyridine is 10.4 hours, whereas in slow acetylators it is 14.8 hours. Sulfapyridine may also be metabolized into 5-hydroxy-sulfapyridine and N-acetyl-5-hydroxy-sulfapyridine. 5-Acetyl-salicylic acid is primarily metabolized in the liver and intestine into N-acetyl-5-aminosalicylic acid, a pathway independent of acetylator phenotype. Due to the low plasma levels of 5-acetyl-salicylic acid achieved after oral administration, it is not possible to reliably estimate its plasma half-life.

Excretion. Absorbed sulfapyridine and 5-aminosalicylic acid and their metabolites are primarily excreted in urine as free metabolites or glucuronide conjugates. Most of the 5-aminosalicylic acid remains in the lumen of the colon and is excreted in feces as 5-aminosalicylic acid and acetyl-5-aminosalicylic acid. The calculated clearance of sulfasalazine after intravenous administration was 1 L/h. Renal clearance accounted for 37% of total clearance.

Special patient groups.

Elderly patients. In elderly patients with rheumatoid arthritis, an extended plasma half-life of sulfasalazine, sulfapyridine, and their metabolites has been observed. The clinical significance of this phenomenon is unknown.

Children. Data from small studies involving children aged 4 years and older with ulcerative colitis and inflammatory bowel disease have been published. Compared to adults, the pharmacokinetics of sulfasalazine and sulfapyridine showed weak correlation with patient age or administered dose. To date, no comparative studies have been conducted to establish whether there is a significant difference in pharmacokinetics between children with juvenile rheumatoid arthritis and adults with rheumatoid arthritis.

Metabolism of sulfapyridine and acetyl-sulfapyridine is mediated by different enzymes, resulting in two distinct populations: individuals with fast metabolism and those with slow metabolism. Approximately 60% of the Caucasian population are slow acetylators. In these individuals, an extended plasma half-life of sulfapyridine (14.8 hours compared to 10.4 hours) and higher plasma levels of sulfapyridine are observed compared to fast acetylators. The clinical significance of this finding is not entirely clear; however, in a small pharmacokinetic study assessing acetylator status, individuals classified as slow acetylators experienced a higher incidence of adverse events.

Sex. Sex does not influence the levels or metabolic profile of sulfasalazine, sulfapyridine, or 5-aminosalicylic acid.

Clinical characteristics.

Indications.

• Treatment of mild to moderate ulcerative colitis and as adjunctive therapy in severe ulcerative colitis; prolongation of the remission period between acute attacks of ulcerative colitis;
• treatment of patients with rheumatoid arthritis in whom salicylates or other nonsteroidal anti-inflammatory drugs (NSAIDs) have been insufficiently effective (e.g., inadequate therapeutic response or intolerance despite appropriate administration of full doses of one or more NSAIDs);
• treatment of juvenile rheumatoid arthritis with polyarticular syndrome when salicylates or other NSAIDs have been insufficiently effective.

Contraindications.

• Hypersensitivity to sulfasalazine, its metabolites, sulfonamides, or salicylates;
• intestinal obstruction or urinary tract obstruction;
• porphyria, as sulfonamides have been reported to precipitate acute attacks;
• severe renal impairment (glomerular filtration rate < 30 mL/min/1.73 m²) and/or severe hepatic impairment;
• history of severe asthma attacks, urticaria, rhinitis, or other allergic reactions induced by acetylsalicylic acid or other NSAIDs, due to the risk of anaphylactic reaction with fatal outcome.

Interaction with other medicinal products and other forms of interaction.

Reduced absorption of folic acid and digoxin has been observed when administered concomitantly with sulfasalazine.

Bone marrow suppression and leukemia have been reported with concomitant use of 6-mercaptopurine or its prodrug azathioprine with orally administered sulfasalazine.

Concomitant administration of 2 g daily doses of sulfasalazine and 7.5 mg weekly doses of methotrexate in 15 patients with rheumatoid arthritis (in a drug interaction study) did not result in changes in pharmacokinetic parameters of these drugs.

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

Laboratory parameters. There have been several reports of a possible influence on laboratory test results (liquid chromatography) of normetanephrine in urine, leading to false-positive results in patients receiving sulfasalazine or its metabolite mesalamine/mesalazine.

Sulfasalazine or its metabolite, sulfapyridine, may interfere with ultraviolet absorption, particularly at 340 nm, and may interfere with certain laboratory tests that use nicotinamide-adenine dinucleotide or nicotinamide-adenine dinucleotide phosphate to measure ultraviolet absorption around this wavelength. Examples of such assays may include determination of alanine aminotransferase, aspartate aminotransferase, creatine kinase muscle/brain, ammonia, thyroxine, or glucose. False laboratory results are possible in patients receiving sulfasalazine doses exceeding the recommended ones.

Special precautions for use.

SALAZOPYRIN EN-tabs is particularly indicated for patients with ulcerative colitis who cannot tolerate plain sulfasalazine tablets due to gastrointestinal intolerance and who show evidence that this intolerance is not primarily related to high serum levels of sulfapyridine and its metabolites; for example, patients experiencing nausea and vomiting upon initiation of treatment or patients in whom dose reduction has not alleviated gastrointestinal side effects. Patients with rheumatoid arthritis or juvenile rheumatoid arthritis should continue to follow recommended rest and physiotherapy regimens as appropriate. Unlike anti-inflammatory drugs, the effect of SALAZOPYRIN EN-tabs does not occur immediately. Concomitant treatment with analgesics and/or nonsteroidal anti-inflammatory drugs is recommended until the therapeutic effect of the drug becomes evident.

Hepatic failure and elevated serum liver enzymes have been reported during treatment with 5-aminosalicylic acid/mesalazine-containing preparations in patients with pre-existing liver disease. Therefore, SALAZOPYRIN EN-tabs is contraindicated in patients with severe hepatic impairment (see "Contraindications"). Caution is required when administering the drug to patients with mild to moderate hepatic impairment, and the drug should only be used if the potential benefit outweighs the risk to the patient. Liver function should be monitored before initiating therapy and periodically during treatment. Renal adverse events, including minimal change nephropathy and chronic interstitial nephritis, have been reported with mesalamine and its prodrugs. SALAZOPYRIN EN-tabs is contraindicated in patients with severe renal impairment (see "Contraindications"). Caution is required when administering the drug to patients with mild to moderate renal impairment, and the drug should only be used if the potential benefit significantly outweighs the risk. Renal function should be monitored before initiating therapy and periodically during treatment. Fatal hypersensitivity reactions, agranulocytosis, aplastic anemia, other blood dyscrasias, hepatic and renal injury, irreversible neuromuscular and central nervous system disorders, and fibrosing alveolitis have been reported in association with sulfasalazine use. The presence of clinical symptoms such as sore throat, fever, pallor, purpura, or jaundice may indicate serious hematological disorders or hepatotoxicity. Patients receiving SALAZOPYRIN EN-tabs should undergo complete blood count and urinalysis with careful microscopic examination. Treatment with sulfasalazine should be discontinued pending blood test results. Discontinuation of SALAZOPYRIN EN-tabs is required if renal function deteriorates during therapy.

Oligospermia and infertility may occur in males receiving sulfasalazine therapy. These effects are reversible upon discontinuation of the drug, typically within 2–3 months.

Serious infections, including fatal sepsis and pneumonia, have been reported. Some infections were associated with agranulocytosis, neutropenia, or myelosuppression. If a serious infection occurs in a patient, the drug should be discontinued. Patients should be closely monitored for signs and symptoms of infection during and after treatment. Any patient who develops a new infection during treatment should undergo immediate and comprehensive diagnostic evaluation to detect infection and myelosuppression. Caution is advised when considering sulfasalazine use in patients with a history of recurrent or chronic infections, or in those with concomitant conditions or medications that may predispose to infection.

Severe hypersensitivity reactions may affect internal organs, leading to hepatitis, nephritis, myocarditis, mononucleosis-like syndrome (pseudomononucleosis), hematological abnormalities (including hemophagocytic histiocytosis), and/or pneumonitis, including eosinophilic infiltration.

Life-threatening systemic hypersensitivity reactions, such as drug rash with eosinophilia and systemic symptoms (DRESS), have been reported in patients receiving sulfasalazine. Even in the absence of skin rash, early signs of hypersensitivity such as fever or lymphadenopathy may occur. If such signs or symptoms appear, the patient should be evaluated immediately. If no alternative cause for these signs or symptoms can be identified, sulfasalazine therapy must be discontinued.

Other serious skin reactions associated with sulfasalazine use, some with fatal outcomes, have been reported, including exfoliative dermatitis, Stevens–Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis (see section "Adverse reactions"). The risk of these events is highest early in therapy, and most cases occur within the first month of treatment.

Sulfasalazine must be discontinued at the first sign or symptom of severe skin reactions or other signs of hypersensitivity, and further evaluation should be considered.

Patients with known hypersensitivity to furosemide, thiazide diuretics, or carbonic anhydrase inhibitors should be monitored for skin rash, mucosal lesions, or other signs of allergic reactions due to possible cross-sensitivity to SALAZOPYRIN EN-tabs.

Precautions.

General. The drug should be administered with caution in patients with severe allergies or bronchial asthma. Adequate fluid intake should be ensured to prevent crystalluria and stone formation. Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency should be closely monitored for signs of hemolytic anemia, which is usually dose-dependent. Treatment should be discontinued immediately if toxic or hypersensitivity reactions occur.

Isolated cases have been reported in which SALAZOPYRIN EN-tabs tablets passed through the gastrointestinal tract without disintegrating. In such cases, drug administration should be discontinued immediately.

Patient information.

Patients should be informed about the possibility of adverse effects and the need for careful medical monitoring. Symptoms such as sore throat, fever, pallor, purpura, or jaundice may indicate serious blood disorders. Patients experiencing any of these symptoms should seek immediate medical attention.

Patients should be instructed to take the drug in two divided doses, preferably after meals, and to swallow the tablets whole. Patients should be informed that sulfasalazine may cause orange-yellow discoloration of urine or skin.

Ulcerative colitis. Patients with ulcerative colitis should be informed that the disease rarely resolves completely, but the risk of relapse may be significantly reduced with long-term maintenance therapy using SALAZOPYRIN EN-tabs.

Rheumatoid arthritis. Rheumatoid arthritis rarely resolves completely. Therefore, long-term therapy is indicated. Ongoing monitoring of patients requiring sulfasalazine should be conducted by physicians to determine the need for continued treatment.

Laboratory tests. Before initiating SALAZOPYRIN EN-tabs and every two weeks during the first three months of therapy, a complete blood count with differential and liver function tests should be performed. During the subsequent three months, these tests should be repeated monthly, then every three months thereafter, and as clinically indicated. Urinalysis and renal function assessment should also be performed periodically during treatment with SALAZOPYRIN EN-tabs.

Serum sulfapyridine level monitoring may be useful, as concentrations above 50 µg/mL are likely associated with an increased frequency of adverse reactions.

Oral sulfasalazine inhibits the absorption and metabolism of folic acid, potentially leading to folic acid deficiency (see section "Use during pregnancy or breastfeeding"), which in turn may result in serious hematological disorders (such as macrocytosis and pancytopenia).

Use during pregnancy or breastfeeding.

Use during pregnancy

Adequate and well-controlled studies of sulfasalazine in pregnant women have not been conducted. Reproductive studies in rats and rabbits showed no evidence of impaired fertility or fetal harm. However, since animal reproductive studies do not always reliably predict human response, this drug should be used during pregnancy only if clearly needed.

Cases of neural tube defects have been reported in children born to mothers who took sulfasalazine during pregnancy, although the role of sulfasalazine in causing these defects has not been established. However, oral sulfasalazine inhibits the absorption and metabolism of folic acid, potentially interfering with folic acid repletion (see section "Interaction with other medicinal products and other forms of interaction") and reducing the efficacy of folic acid supplements taken before and after conception, which are known to reduce the risk of neural tube defects.

A study of 1455 pregnancies exposed to sulfonamides, including sulfasalazine, showed no apparent increase in congenital malformations associated with use of this drug class. A review of medical literature including data from 1155 pregnant women with ulcerative colitis indicates that pregnancy outcomes were not different from those expected in the general population.

No clinical studies have evaluated the effects of sulfasalazine on growth, development, and functional maturation in children whose mothers received the drug during pregnancy.

Clinical observations. Sulfasalazine and its metabolite sulfapyridine cross the placenta and are also present in breast milk. In newborns, sulfonamides compete with bilirubin for protein binding sites in plasma and may cause kernicterus. Although sulfapyridine has been shown to have low bilirubin-displacing capacity, newborns should be monitored for signs of kernicterus.

A case of agranulocytosis in a newborn whose mother took sulfasalazine and prednisone during pregnancy has been reported.

Use during breastfeeding

Sulfonamides, including sulfasalazine, are excreted in breast milk (see section "Use during pregnancy", "Clinical observations"). Only small amounts of sulfasalazine are detected in milk, whereas levels of the active metabolite sulfapyridine in milk are approximately 30–60% of maternal serum levels. SALAZOPYRIN EN-tabs should be used with caution in nursing women.

There have been limited reports of bloody stools or diarrhea in infants breastfed by mothers receiving sulfasalazine. In reported cases, bloody stools or diarrhea in the infant resolved after discontinuation of sulfasalazine by the mother or cessation of breastfeeding. Due to limited data, a causal relationship between sulfasalazine use and bloody stools or diarrhea cannot be confirmed or ruled out.

Infants breastfed by mothers taking sulfasalazine should be monitored for signs and symptoms of diarrhea and/or bloody stools.

Ability to affect reaction speed when driving or operating machinery.

The effect of sulfasalazine on the ability to drive or operate machinery has not been systematically evaluated.

Method of Administration and Dosage

Route of administration: Oral use.

The dosage of SALAZOPYRIN EN-tabs tablets should be adjusted according to individual patient response and tolerability.

Patients should be instructed to take SALAZOPYRIN EN-tabs in two divided doses, preferably after meals, swallowing the tablets whole.

Ulcerative colitis

Initial therapy

Adults: 3–4 g daily in equally divided doses administered at intervals not exceeding 8 hours. It may be advisable to initiate therapy at lower doses, e.g., 1–2 g daily, to minimize possible gastrointestinal intolerance. If a daily dose exceeding 4 g is required to achieve the desired therapeutic effect, the increased risk of toxic reactions should be taken into account.

Children aged 6 years and older: 40–60 mg/kg body weight per 24-hour period, divided into 3–6 doses. The medication is not recommended for children whose single dose, calculated according to body weight, is less than 1 tablet (500 mg).

Maintenance therapy

Adults: 2 g daily.

Children aged 6 years and older: 30 mg/kg body weight per 24-hour period, divided into 4 doses. The medication is not recommended for children whose single dose, calculated according to body weight, is less than 1 tablet (500 mg).

The efficacy of SALAZOPYRIN EN-tabs in acute ulcerative colitis can be assessed by clinical criteria, including presence of elevated body temperature, changes in body weight, degree and frequency of diarrhea and bleeding, as well as by sigmoidoscopy findings and biopsy results. Continued administration of the drug is often necessary even after clinical symptoms, including diarrhea, have been controlled. If endoscopic examination confirms satisfactory improvement, the dose of SALAZOPYRIN EN-tabs should be reduced to the maintenance level. If diarrhea recurs, the dose should be increased to the previously effective dose.

SALAZOPYRIN EN-tabs is particularly indicated for patients who cannot tolerate uncoated sulfasalazine tablets due to gastrointestinal intolerance (e.g., loss of appetite, nausea). If gastrointestinal intolerance symptoms (loss of appetite, nausea, vomiting, etc.) occur during the initial doses of SALAZOPYRIN EN-tabs, they are likely due to elevated serum sulfapyridine levels and may be minimized by halving the daily dose initially, followed by gradual dose escalation over several days. If gastrointestinal intolerance persists, administration of the drug should be discontinued for 5–7 days, then restarted at a lower daily dose.

Rheumatoid arthritis in adults

2 g daily in two equal doses. It is recommended to initiate therapy at lower doses of SALAZOPYRIN EN-tabs, e.g., 0.5–1 g daily, to minimize possible gastrointestinal intolerance. The recommended dosage regimen is provided below.

In rheumatoid arthritis, the effect of SALAZOPYRIN EN-tabs can be assessed by the degree of improvement and the number and severity of joints with active inflammation. Therapeutic efficacy may be observed as early as 4 weeks after initiation of treatment; however, in some patients, up to 12 weeks of treatment may be required before clinical benefits become evident. An increase in the daily dose up to 3 g may be considered if clinical efficacy is insufficient after 12 weeks. Close monitoring of the patient is recommended when doses exceeding 2 g daily are used.

Recommended dosage regimen for rheumatoid arthritis in adults:

Juvenile rheumatoid arthritis with polyarticular syndrome

The drug is not recommended for children whose single dose, calculated according to body weight, is less than 1 tablet (500 mg).

Children aged 6 years and older: 30–50 mg/kg body weight per day, divided into 2 equal doses. The usual maximum dose is 2 g per day. To reduce the potential gastrointestinal intolerance, therapy should be initiated at one-quarter or one-third of the planned maintenance dose, increasing the dose weekly until the maintenance dose is reached within one month.

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

Children.

The safety and efficacy of the drug in patients under 2 years of age with ulcerative colitis have not been established.

The safety and efficacy of the drug in the treatment of signs and symptoms of juvenile rheumatoid arthritis with polyarticular syndrome in patients aged 6 to 16 years are supported 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 polyarticular syndrome is based on the similarity of the disease and treatment response in these two patient groups. Published study results support the possibility of extrapolating safety and efficacy data for sulfasalazine in juvenile rheumatoid arthritis with polyarticular syndrome (see section "Adverse reactions").

A high frequency of adverse events has been reported in patients with systemic-onset juvenile arthritis. The use of the drug in children with systemic-onset juvenile rheumatoid arthritis frequently led to a serum sickness-like reaction. This reaction was often severe and manifested by fever, nausea, vomiting, headache, rash, and abnormal liver function test results. Treatment with sulfasalazine in systemic-onset juvenile rheumatoid arthritis is not recommended.

Overdose.

Evidence indicates 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, gastric distress, and abdominal pain. In more severe cases, central nervous system symptoms such as drowsiness, seizures, etc., may occur. Serum sulfapyridine concentrations can be used to monitor recovery after overdose.

Patients with impaired renal function are at increased risk of developing severe toxicity.

There are no documented reports of fatalities due to ingestion of large single doses of sulfasalazine. The LD50 could not be determined in laboratory animals, including mice, since the highest oral daily dose of sulfasalazine that could be administered (12 g/kg) did not result in death. Chronic administration of sulfasalazine at a dose of 16 g per day in tablet form did not result in fatalities in patients.

Overdose management. Gastric lavage or induction of emesis and administration of cathartics, if indicated. Alkalinization of urine. With normal renal function, intensive hydration should be performed. In the presence of oliguria, fluid and electrolyte intake should be restricted, and appropriate treatment initiated. In cases of complete ureteral obstruction by crystals, ureteral catheterization may be performed. The low molecular weight of sulfasalazine and its metabolites may facilitate their removal by dialysis.

Patients should be evaluated for signs of methemoglobinemia or sulfhemoglobinemia. If these conditions are present, appropriate therapy should be administered.

Adverse Reactions

The most common adverse reactions associated with sulfasalazine use in ulcerative colitis were loss of appetite, headache, nausea, vomiting, gastrointestinal disturbances, and reversible oligospermia. These reactions occurred in approximately one-third of patients. Less frequently observed adverse reactions included pruritus, urticaria, rash, fever, Heinz body anemia, hemolytic anemia, and cyanosis (occurring in 1 out of 30 patients or fewer). Experience indicates that the frequency of adverse reactions tends to increase with daily doses of 4 g or higher, or when serum sulfapyridine levels exceed 50 mcg/mL.

Sulfasalazine use in adult rheumatoid arthritis was associated with similar adverse reactions, although the incidence of individual reactions was higher. In rheumatoid arthritis studies, the following adverse reactions were commonly reported: nausea (19%), dyspepsia (13%), rash (13%), headache (9%), abdominal pain (8%), vomiting (8%), fever (5%), dizziness (4%), stomatitis (4%), pruritus (4%), abnormal liver function tests (4%), leukopenia (3%), and thrombocytopenia (1%). One case of 10% immunoglobulin suppression was reported. This reaction had a slow reversible course and rarely was associated with clinical symptoms.

Overall, adverse reactions in patients with juvenile rheumatoid arthritis were similar to those observed in adult patients with rheumatoid arthritis, except for a higher incidence of serum sickness-like syndrome in systemic-onset juvenile rheumatoid arthritis. In one clinical study, a 10% rate of immunoglobulin suppression was observed.

Although only a limited number of adverse reactions are listed below that have been reported with this specific medicinal product, the pharmacological similarity of sulfonamides suggests that each of these reactions should be considered when using SALAZOPYRIN EN-tabs.

Adverse reactions occurring uncommonly or rarely

Infections and infestations: aseptic meningitis, pseudomembranous colitis.

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

Immune system disorders: erythema multiforme, epidermal necrolysis (Stevens-Johnson syndrome/toxic epidermal necrolysis) with corneal involvement, exfoliative dermatitis, drug rash with eosinophilia and systemic symptoms (DRESS), anaphylaxis, serum sickness-like syndrome, interstitial lung disease, pneumonitis with or without eosinophilia, vasculitis, fibrosing alveolitis, pleuritis, pericarditis with or without tamponade, allergic myocarditis, polyarteritis nodosa, lupus-like syndrome, hepatitis and liver necrosis with or without immune complexes, fulminant hepatitis sometimes leading to liver transplantation, acute generalized exanthematous pustulosis (Muche-Garbe syndrome), rhabdomyolysis, photosensitization, arthralgia, periorbital edema, injection of conjunctiva and sclera, alopecia, and hypersensitivity reactions.

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

Psychiatric disorders: depression.

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

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

Other reactions: change in urine color, change in skin color, erythema, alopecia, facial swelling.

Sulfonamides have defined chemical similarities with some goitrogenic agents, diuretics (acetazolamide and thiazides), and oral hypoglycemic agents. Rarely, goiter enlargement, hypoglycemia, and diuresis may occur in patients receiving sulfonamides.

Cross-sensitivity with these agents may occur. Rats appear particularly sensitive to the goitrogenic effects of sulfonamides, and prolonged administration in this species has led to malignant thyroid tumors.

Post-marketing reports

The following events have been identified during post-marketing clinical use of medicinal products containing mesalazine (or metabolized to mesalazine). As these reports are submitted voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency. These events are included based on a combination of factors such as severity, reporting frequency, or potential causal relationship to mesalazine.

Blood and lymphatic system disorders: pseudomononucleosis.

Cardiac disorders: myocarditis.

Hepatobiliary disorders: reports of hepatotoxicity, including elevated liver function tests (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), jaundice, cholestatic jaundice, cirrhosis, cholestatic hepatitis, cholestasis, and possible hepatocellular injury including liver necrosis and hepatic failure. Some of these cases resulted in fatal outcomes. One case of Kawasaki-like syndrome including liver function abnormalities has been reported.

Immune system disorders: anaphylaxis.

Metabolism and nutritional disorders: loss of appetite, folate deficiency.

Renal and urinary disorders: nephrolithiasis.

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

Skin and subcutaneous tissue disorders: angioneurotic edema, purpura, toxic epidermal necrolysis/Stevens-Johnson syndrome, exfoliative dermatitis, drug rash with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis, toxic pustular dermatosis, lichen planus, photosensitivity, Sjögren-Larsson syndrome.

Vascular disorders: pallor.

Drug misuse and dependence: not reported.

Laboratory investigations: elevated liver enzymes, induction of autoantibodies.

Reporting of adverse reactions

Reporting of adverse reactions after medicinal product registration is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, and patients or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

5 years.

Storage conditions.

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

Packaging.

100 tablets in a bottle. One bottle in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Recipharm Uppsala AB /
Recipharm Uppsala AB.

Manufacturer's address and place of business.

Bjorkgatan 30, Uppsala Domkyrkofors, Uppsala, 753 23, Sweden /
Bjorkgatan 30, Uppsala Domkyrkofors, Uppsala, 753 23, Sweden.