Sulfasalazine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Sulfasalazine (Sulfasalazin)

Composition:

Active substance: sulfasalazine;

1 tablet contains 500 mg of sulfasalazine;

Excipients: povidone, pregelatinized starch, magnesium stearate, colloidal anhydrous silicon dioxide, hypromellose, propylene glycol.

Pharmaceutical form. Film-coated tablets.

Main physico-chemical characteristics: round, brownish-yellow, slightly biconvex tablets with bevelled edges, coated with a transparent, colorless film layer.

Pharmacotherapeutic group.

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

ATC code A07EC01.

Pharmacological Properties.

Pharmacodynamics.

Sulfasalazine is an anti-inflammatory agent. It exerts an immunosuppressive effect, particularly in connective tissue, intestinal wall, and serous fluid, where its concentration is highest. Due to intestinal flora, sulfasalazine is split into sulfapyridine and 5-aminosalicylic acid. Sulfapyridine suppresses proliferation of killer cells and lymphocyte transformation. The anti-inflammatory action of 5-aminosalicylic acid (mesalazine) is particularly important for the treatment of inflammatory diseases of the large intestine. Locally, it primarily inhibits cyclooxygenase and lipoxygenase in the intestinal wall, thereby preventing the formation of prostaglandins, leukotrienes, and other inflammatory mediators. It may also bind free oxygen radicals.

Pharmacokinetics.

Approximately 30% of the administered dose of sulfasalazine is absorbed in the small intestine; the remaining 70% is metabolized by intestinal flora in the colon into sulfapyridine and 5-aminosalicylic acid. Maximum plasma concentrations of sulfasalazine and its metabolites vary considerably between patients—those with low acetylation capacity have significantly higher levels, which are associated with a higher incidence of adverse effects. Sulfasalazine is highly bound to plasma proteins and connective tissue. Most of the absorbed amount is excreted via bile into the intestine; a small portion is excreted unchanged in the urine. The elimination half-life of sulfasalazine ranges from 5 to 10 hours.

The majority of released sulfapyridine is absorbed and reaches peak serum concentration 12–24 hours after drug administration. It is metabolized in the liver (via acetylation, hydroxylation, and conjugation with glucuronic acid) and excreted by the kidneys. The elimination half-life ranges from 6 to 14 hours, depending on acetylation rate. Only about 30% of 5-aminosalicylic acid is absorbed, acetylated in the liver, and excreted by the kidneys in urine. The remainder is excreted unchanged in feces.

Clinical characteristics.

Indications.

• Induction and maintenance of remission in ulcerative colitis; treatment of Crohn's disease in active stage.
• Treatment of rheumatoid arthritis in adults when nonsteroidal anti-inflammatory drugs (NSAIDs) have been insufficiently effective.
• Treatment of juvenile polyarticular or oligoarticular rheumatoid arthritis.

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/1.73m²) and/or severe hepatic impairment.
• Patients with a history of severe asthma attacks, urticaria, rhinitis, or other allergic reactions induced by acetylsalicylic acid or other NSAIDs. Anaphylactic reactions with fatal outcomes have been reported in such patients.
• Children under 6 years of age.

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 prodrugs, azathioprine, with sulfasalazine (oral administration).

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 in 310 patients with rheumatoid arthritis in 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 interference with laboratory test results (liquid chromatography) of urinary normetanephrine, leading to false-positive results in patients receiving sulfasalazine or its metabolite, mesalamine/mesalazine.

Special precautions for use.

Sulfasalazine 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 who experience nausea and vomiting upon initial doses of the drug, or patients in whom dose reduction has not alleviated gastrointestinal side effects. Patients with rheumatoid arthritis or juvenile rheumatoid arthritis should continue to follow rest and physical therapy regimens as indicated. Unlike anti-inflammatory drugs, the therapeutic effect of Sulfasalazine is not immediate. Concomitant treatment with analgesics and/or NSAIDs is recommended at least until the drug's effect becomes apparent.

Cases of liver failure and elevated serum liver enzymes have been reported during treatment with 5-aminosalicylic acid/mesalazine products in patients with a history of liver disease. Therefore, Sulfasalazine is contraindicated in patients with severe hepatic impairment (see section "Contraindications"). Caution should be exercised when administering the drug to patients with moderate to moderate-to-severe liver impairment, and the drug should only be used if the therapeutic benefit clearly outweighs the potential risk. 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. Sulfasalazine is contraindicated in patients with severe renal impairment (see section "Contraindications"). Caution is advised when using the drug in patients with moderate to moderate-to-severe renal impairment, and treatment should only be initiated if the benefit clearly outweighs the risk. Renal function should be monitored before starting therapy and periodically during treatment.

Fatal reactions associated with sulfasalazine use, including hypersensitivity reactions, agranulocytosis, aplastic anemia, other blood dyscrasias, liver and kidney damage, irreversible neuromuscular and central nervous system disorders, and fibrosing alveolitis, have been reported. Clinical symptoms such as sore throat, fever, pallor, purpura, or jaundice may indicate serious blood disorders or hepatotoxicity. Patients receiving Sulfasalazine should undergo complete blood count and urinalysis with careful microscopic examination. Treatment with sulfasalazine should be discontinued pending laboratory test results.

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 sepsis with fatal outcomes and pneumonia, have been reported. Some infections were associated with agranulocytosis, neutropenia, or myelosuppression. If a patient develops a serious infection, sulfasalazine 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 while on therapy should undergo immediate and comprehensive diagnostic evaluation to rule out infection and myelosuppression. Caution should be exercised when considering sulfasalazine use in patients with a history of recurrent or chronic infections, concomitant diseases, or those receiving other medications that may increase infection risk.

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.

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

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

Severe, 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, prompt patient evaluation is required. If no alternative cause can be identified, sulfasalazine therapy should be discontinued.

Patients with known hypersensitivity to furosemide, thiazide diuretics, or carbonic anhydrase inhibitors should be monitored for skin rash, mucosal lesions, or other allergic manifestations due to possible cross-sensitivity to sulfasalazine.

Precautionary measures.

General considerations. The drug should be prescribed 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 with the drug should be discontinued immediately in case of toxic or hypersensitivity reactions.

Patient information.

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

Patients should be instructed to divide the dose into two equal administrations. Tablets should be swallowed whole, preferably with meals. 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 flare-ups may be significantly reduced with long-term maintenance therapy using Sulfasalazine.

Rheumatoid arthritis. Rheumatoid arthritis rarely resolves completely. Therefore, long-term treatment may be necessary. Physicians should continue monitoring patients on sulfasalazine to determine the need for prolonged therapy.

Laboratory tests. Before initiating Sulfasalazine therapy, and every two weeks during the first three months of treatment, a complete blood count with differential and liver function tests should be performed. During the following three months, these tests should be repeated monthly, and thereafter every three months or as clinically indicated. Periodic urinalysis and renal function assessment should also be performed during treatment with Sulfasalazine (see section "Effect on laboratory test results" below).

Serum sulfapyridine level monitoring may be useful, as concentrations above 50 µg/mL are likely associated with an increased incidence 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") and possibly contributing to serious hematological disorders such as macrocytosis and pancytopenia.

Effect on laboratory test results

There have been several reports of possible interference by sulfasalazine or its metabolite mesalamine with urinary normetanephrine testing by liquid chromatography, leading to false-positive results.

Sulfasalazine or its metabolites may interfere with ultraviolet light absorption, particularly at 340 nm, and may interfere with laboratory assays that use NAD(H) or NADP(H) for measuring ultraviolet absorption near this wavelength. Examples of such assays include those for urea, ammonia, LDH, α-HBDH, and glucose. During high-dose sulfasalazine therapy, interference with alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase muscle/brain (CK-MB), glutamate dehydrogenase (GLDH), or thyroxine may occur. Consultation with the laboratory regarding methodology is recommended. When evaluating laboratory results in patients receiving sulfasalazine, this potential interference should be considered. Results should be interpreted in conjunction with clinical findings.

Use during pregnancy or breastfeeding.

Pregnancy

Published data on sulfasalazine use in pregnant women show no evidence of teratogenic risk. The likelihood of adverse fetal effects with sulfasalazine use during pregnancy is low. However, oral sulfasalazine inhibits the absorption and metabolism of folic acid and may lead to folic acid deficiency. Since harmful effects cannot be completely ruled out, sulfasalazine should be used during pregnancy only if clearly needed.

Breastfeeding period

Sulfasalazine and sulfapyridine are excreted in breast milk. The drug should be used with caution in breastfeeding women, particularly when nursing premature infants or infants with glucose-6-phosphate dehydrogenase deficiency. The decision to breastfeed should be made by the physician, weighing the benefit-risk ratio for both mother and infant.

Ability to affect reaction speed when driving or operating machinery.

The effect of sulfasalazine on reaction speed during driving or operating machinery has not been systematically evaluated.

Administration and Dosage.

The dose should be adjusted according to the severity of the disease and possible adverse effects. Tablets should be taken during meals with a glass of liquid. A missed dose should be taken as soon as possible, provided that sufficient time remains before the next scheduled dose. In such a case, the patient should take only the next scheduled dose.

Tablets should be swallowed whole, without breaking or crushing.

Elderly patients: no special precautions are required.

Ulcerative colitis

Adults

Severe disease: 2–4 tablets of Sulfasalazine 4 times daily. Concomitant use with corticosteroids may be considered as part of intensive therapy. The efficacy of the drug may be reduced if tablets pass through the gastrointestinal tract too quickly.

The nighttime interval between doses should not exceed 8 hours.

Moderate disease: 2–4 tablets 4 times daily, with or without corticosteroids.

Mild disease: 2 tablets 4 times daily, with or without corticosteroids.

Maintenance therapy: after induction of remission, the dose should be gradually reduced to 4 tablets per day. This dose should be continued indefinitely, as discontinuation of treatment—even several years after an acute attack—increases the risk of relapse by 4 times.

Children

Dosage should be reduced proportionally to body weight.

In case of acute attack or relapse: 40–60 mg/kg/day.

Maintenance treatment: 20–30 mg/kg/day.

Crohn’s disease

Sulfasalazine should be administered according to the same regimen as for ulcerative colitis (see above).

Rheumatoid arthritis

Adults

Patients with rheumatoid arthritis, especially those who have been on long-term NSAID therapy, may have a sensitive stomach. Therefore, Sulfasalazine should be initiated according to the following recommendations. Treatment should begin with 1 tablet daily, increasing the dose by 1 tablet daily each week until reaching either 1 tablet 4 times daily or 2 tablets 3 times daily, depending on tolerability and efficacy. The effect develops slowly, and a noticeable improvement may not occur within the first 6 weeks. Improvement in joint mobility should be accompanied by a reduction in erythrocyte sedimentation rate and C-reactive protein levels. Concomitant use of NSAIDs with Sulfasalazine is possible.

Juvenile polyarticular or oligoarticular rheumatoid arthritis.

Children aged 6 years and older.

30–50 mg/kg/day, divided into 4 equal doses. The usual maximum daily dose is 2000 mg/day. To minimize gastrointestinal intolerance, treatment should be initiated at ¼ of the intended maintenance dose, increasing by ¼ each week until the maintenance dose is reached.

Children.

Studies on the safety and efficacy of sulfasalazine in treating signs and symptoms of juvenile rheumatoid arthritis with polyarticular syndrome in patients aged 6 to 16 years have been reported. 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 of sulfasalazine in juvenile rheumatoid arthritis with polyarticular syndrome (see section "Adverse Reactions").

A high frequency of adverse events has been observed in patients with systemic-onset juvenile arthritis. Treatment with sulfasalazine in children with systemic-onset juvenile rheumatoid arthritis often leads to a reaction resembling serum sickness. This reaction is often severe and manifests as fever, nausea, vomiting, headache, rash, and abnormal liver function tests. Sulfasalazine is not recommended for use in children with systemic-onset juvenile rheumatoid arthritis.

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 disturbances, 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 severe toxicity.

There are no documented reports of fatalities due to ingestion of large single doses of sulfasalazine. The LD50 in laboratory animals, particularly mice, could not be determined because the highest oral daily dose of sulfasalazine administered (12 g/kg) did not result in death. Chronic administration of sulfasalazine up to 16 g daily in tablet form has not resulted in fatalities in patients.

Overdose management. If indicated, gastric lavage or induction of emesis and administration of laxatives may be performed. Alkalinization of urine is recommended. With normal renal function, intensive hydration is necessary. In cases of oliguria, fluid and saline 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 elimination via dialysis.

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

Adverse Reactions

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

In the treatment of rheumatoid arthritis in adults, sulfasalazine has been associated with similar adverse reactions, although the frequency of certain individual reactions was higher. Commonly reported adverse reactions in rheumatoid arthritis studies included: 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 report described a 10% reduction in immunoglobulin levels. This reaction developed slowly and rarely was associated with clinical symptoms.

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

Although only a limited number of adverse reactions are listed below, the pharmacological similarity of sulfonamides suggests that all such reactions should be considered possible during treatment with sulfasalazine.

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 (Stevens-Johnson syndrome), exfoliative dermatitis, epidermal necrolysis (Lyell's syndrome) with corneal damage, drug rash with eosinophilia and systemic symptoms (DRESS), anaphylaxis, serum sickness-like reaction, 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 requiring liver transplantation), acute papulopustular parapsoriasis (Muche-Haberman syndrome), rhabdomyolysis, photosensitivity, arthralgia, periorbital edema, conjunctival and scleral injection, alopecia, hypersensitivity reactions.

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

Psychiatric disorders: depression.

Central nervous system disorders: taste disturbances, transverse myelitis, seizures, meningitis, posterior spinal cord involvement, 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: changes in urine color and skin discoloration.

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

Cross-sensitivity with these agents may occur. Rats appear to be 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 use of mesalazine-containing (or mesalazine-metabolizing) products in clinical practice. Because these reports are voluntary and submitted from a population of uncertain size, it is not possible to reliably estimate their frequency. These events are included due to a combination of factors such as seriousness, frequency of reporting, 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 (AST/SGOT, ALT/SGPT, 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 death. One case of a Kawasaki-like syndrome, including liver function abnormalities, has been reported.

Immune system disorders: anaphylaxis.

Metabolism and nutrition 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, exanthema, toxic pustular dermatosis, lichen planus, photosensitivity, Sjögren-Larsson syndrome.

Vascular disorders: pallor.

Drug abuse and dependence: not reported.

Laboratory findings: elevated liver enzymes, induction of autoantibodies.

Shelf life. 5 years.

Storage conditions.

Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto / KRKA, d.d., Novo mesto.

Manufacturer's address and location of operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.