Instructions for use Salazopyrin-EN-tabs enteric-coated tablets 500 mg bottle No. 100
Composition
active ingredient: sulfasalazine;
1 tablet contains sulfasalazine 500 mg, which corresponds to 535 mg of sulfasalazine with povidone;
Excipients: pregelatinized starch, magnesium stearate, colloidal anhydrous silicon dioxide, cellulose acetylphthalate, propylene glycol, talc, macrogol, carnauba wax, glycerol monostearate, white wax.
Dosage form
The film-coated tablets are enteric-coated.
Main physicochemical properties: yellow-orange elliptical convex tablets, coated with an enteric coating, marked with the letters “КРh” on one side and the drug code “102” on the other.
Pharmacotherapeutic group
Anti-inflammatory drugs used in intestinal diseases. Aminosalicylic acid and similar drugs.
ATX code A07E C01.
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, to its affinity for connective tissue, and/or to the relatively high concentrations achieved in serous fluids, liver, and intestinal wall as demonstrated in radioautographic studies in animals. Clinical studies in ulcerative colitis involving rectal administration of sulfasalazine, sulfapyridine, and 5-aminosalicylic acid have shown that the major therapeutic effect may be due to the 5-aminosalicylic acid molecule. The relative contribution of the parent drug and the major metabolites in rheumatoid arthritis is unknown.
Pharmacokinetics.
In vivo studies have shown that the absolute bioavailability of sulfasalazine when administered orally is less than 15% of the parent drug. In the intestine, sulfasalazine is metabolized by intestinal bacteria to form sulfapyridine and 5-aminosalicylic acid. Of the two, sulfapyridine is relatively well absorbed from the intestine and more extensively metabolized, while 5-aminosalicylic acid is much less well absorbed.
Absorption: Following oral administration of 1 g of sulfasalazine to 9 healthy male subjects, less than 15% of the sulfasalazine dose was absorbed as parent drug.
Detectable serum concentrations of sulfasalazine were achieved within 90 minutes of oral administration in healthy subjects. Peak concentrations of sulfasalazine were observed between 3 and 12 hours after oral administration, with a mean peak concentration (6 μg/mL) occurring at 6 hours. Peak plasma levels of sulfapyridine and 5-aminosalicylic acid, however, occurred approximately 10 hours after administration. This longer time to peak concentration suggests that the drug passes through the gastrointestinal tract to the lower intestine, where it is metabolized by bacteria. Sulfapyridine is well absorbed from the large intestine with an estimated bioavailability of 60%. According to the same study, 5-aminosalicylic acid is much less well absorbed from the gastrointestinal tract, with an estimated bioavailability of 10–30%.
Distribution: After intravenous injection, the estimated volume of distribution for sulfasalazine was 7.5 ± 1.6 L. Sulfasalazine is extensively bound to albumin (> 99.3%), whereas sulfapyridine is only approximately 70% bound to albumin. Acetylsulfapyridine, the major metabolite of sulfapyridine, is approximately 90% bound to plasma proteins.
Elimination. Absorbed sulfapyridine and 5-aminosalicylic acid and their metabolites are primarily excreted in the urine as free metabolites or glucuronide conjugates. Most of the 5-aminosalicylic acid remains in the lumen of the large intestine and is excreted in the feces as 5-aminosalicylic acid and acetyl-5-aminosalicylic acid. The estimated clearance of sulfasalazine after intravenous administration was 1 L/h. Renal clearance was estimated to be 37% of total clearance.
Special patient groups.
Elderly: Elderly patients with rheumatoid arthritis have been shown to have a prolonged plasma half-life of sulfasalazine, sulfapyridine, and their metabolites. The clinical impact of this phenomenon is unknown.
Children. Small studies have been published in children aged 4 years and older with ulcerative colitis and inflammatory bowel disease. Compared with adults, the pharmacokinetics of sulfasalazine and sulfapyridine were poorly correlated with patient age or dose. To date, no comparative studies have been conducted to determine whether there is a significant difference in pharmacokinetics between children with juvenile rheumatoid arthritis and adults with rheumatoid arthritis.
The metabolism of sulfapyridine and acetylsulfapyridine is carried out by different enzymes, so two populations are distinguished: individuals with rapid metabolizers and individuals with slow metabolizers. Approximately 60% of the Caucasian population can be attributed to individuals with a slow acetylation phenotype. These individuals will be observed
prolonged plasma half-life of sulfapyridine (14.8 hours vs. 10.4 hours) and accumulation of higher plasma levels of sulfapyridine compared with rapid acetylators. The clinical significance of this finding is uncertain; however, in a small pharmacokinetic study that assessed acetylation status, participants who were slow sulfapyridine acetylators had a higher incidence of adverse events.
Gender: Gender does not affect the levels and structure of metabolites of sulfasalazine, sulfapyridine, or 5-aminosalicylic acid.
Indication
Treatment of mild to moderate ulcerative colitis and as adjunctive therapy in severe ulcerative colitis; prolongation of the period 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 been insufficiently effective (e.g., insufficient therapeutic efficacy or intolerance to appropriate full doses of one or more NSAIDs);
treatment of juvenile rheumatoid arthritis with polyarthritic syndrome in cases where salicylates or other NSAIDs were not 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 during an acute attack;
Severe renal impairment (glomerular filtration rate < 30 ml/min/1.73 m2) and/or severe liver impairment;
history of severe asthma attacks, urticaria, rhinitis or other allergic reactions caused by acetylsalicylic acid or other NSAIDs, due to the risk of developing anaphylactic reactions with a fatal outcome.
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 azathioprine with sulfasalazine (oral administration).
Coadministration of daily doses of sulfasalazine 2 g and weekly doses of methotrexate 7.5 mg in 15 patients with rheumatoid arthritis (in a drug interaction study) did not alter the pharmacokinetics of these drugs.
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 to 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.
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 tests may include measurements of alanine aminotransferase, aspartate aminotransferase, muscle/brain creatine kinase, ammonia, thyroxine, or glucose. Erroneous laboratory results may occur in patients receiving doses of sulfasalazine that exceed those recommended.
Application features
SALAZOPYRIN EN-tabs 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, e.g. patients with nausea and vomiting during the first few doses of the drug or patients in whom dose reduction has not reduced gastrointestinal side effects. Patients with rheumatoid arthritis or juvenile rheumatoid arthritis should continue to maintain a rest regimen and physiotherapy as indicated. Unlike anti-inflammatory drugs, the effect of SALAZOPYRIN EN-tabs is not observed immediately. Concomitant treatment with analgesics and/or non-steroidal anti-inflammatory drugs is recommended at least until the drug has had an effect.
Liver failure and increased serum enzyme levels have been reported during treatment with 5-aminosalicylic acid/mesalazine derivatives in patients with a history of liver disease. Therefore, SALAZOPYRIN EN-tabs 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 only be used 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 damage, including minimal change nephropathy and chronic interstitial nephritis, have been associated with the use of mesalamine and its prodrugs. SALAZOPYRIN EN-tabs 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. Fatalities due to hypersensitivity reactions, agranulocytosis, aplastic anemia, other blood dyscrasias, liver and kidney damage, irreversible changes in the neuromuscular and central nervous systems, 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 SALAZOPYRIN EN-tabs should have a complete blood count and urinalysis with careful microscopic examination. Sulfasalazine treatment should be discontinued while awaiting the results of the blood test. It is necessary to stop taking SALAZOPYRIN EN-tabs if kidney function deteriorates during therapy.
Oligospermia and infertility may occur in men treated with sulfasalazine. These effects reverse within 2–3 months after discontinuation of the drug.
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 detect 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.
Severe, life-threatening systemic hypersensitivity reactions, such as drug rash 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.
Other serious skin reactions, some fatal, have been reported with sulfasalazine, including exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis, and acute generalized exanthematous pustulosis (see section 4.8). The risk of these events is highest early in therapy, with most occurring within the first month of treatment.
Sulfasalazine should be discontinued at the first appearance of signs and symptoms of severe skin adverse reactions or other signs of hypersensitivity and further evaluation should be considered.
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 due to possible hypersensitivity to SALAZOPYRIN EN-tabs in such patients.
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 SALAZOPYRIN EN-tabs tablets not disintegrating during passage through the gastrointestinal tract. In such cases, the use of 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 observation. The appearance of 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 rarely disappears completely, and the risk of exacerbation may be significantly reduced after long-term use of SALAZOPYRIN EN-tabs in 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 treatment with SALAZOPYRIN EN-tabs and every two weeks during the first three months of therapy, a complete blood count with leukocyte formula and liver function tests should be performed. During the next three months, the same tests should be performed once a month, and then every three months and according to clinical indications. Also, periodically during treatment with SALAZOPYRIN EN-tabs, a complete urine test and assessment of kidney 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. This may lead to folic acid deficiency (see section "Use during pregnancy and lactation"), which in turn can lead to the development of serious blood disorders (such as macrocytosis and pancytopenia).
Use during pregnancy or breastfeeding
Use during pregnancy
There have been reports of neural tube defects in children born to mothers who took sulfasalazine during pregnancy, but the role of sulfasalazine in these defects is not established. However, oral sulfasalazine inhibits the absorption and metabolism of folic acid, which may interfere with the replenishment of folic acid levels in the body (see section 4.5) and reduces the effect of folic acid supplements taken before and after conception, which have been shown to reduce the risk of neural tube defects.
A study of 1455 pregnancies in which sulfonamides, including sulfasalazine, were used showed that this class of drugs does not appear to be associated with fetal malformations. A review of the medical literature, which included data from 1155 pregnant women with ulcerative colitis, suggests that pregnancy outcomes were no different from those expected in the general population.
No clinical studies have been conducted on the effects of sulfasalazine on the growth, development, and functional maturation of 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 binding sites on plasma proteins and may cause kernicterus. Although the bilirubin-displacing capacity of sulfapyridine has been shown to be small, newborns should be observed for signs of kernicterus.
A case of agranulocytosis has been reported in a child whose mother took sulfasalazine and prednisone during pregnancy.
Use during breastfeeding
Sulfonamides, including sulfasalazine, are excreted in breast milk (see section "Use during pregnancy." "Clinical observations"). A small amount of sulfasalazine was detected in milk, while the levels of the active metabolite, sulfapyridine, in milk were about 30-60% of its level in maternal serum. SALAZOPYRIN EN-tabs should be used with caution in breastfeeding women.
There have been limited reports of bloody stools or diarrhea in infants breastfed by mothers taking sulfasalazine. In the reported cases where such reactions have been reported, the bloody stools or diarrhea in the infant resolved after the mother stopped taking sulfasalazine or stopped breastfeeding. Due to the limited data, a causal relationship between sulfasalazine and bloody stools or diarrhea cannot be confirmed or ruled out.
Breastfed infants of mothers taking sulfasalazine should be observed for signs and symptoms of diarrhea and/or bloody stools.
The ability to influence the reaction speed when driving or working with other mechanisms
The effect of sulfasalazine on the reaction rate when driving or operating other mechanisms has not been systematically evaluated.
Method of administration and doses
Route of administration: orally.
The dose of SALAZOPYRIN EN-tabs tablets should be adjusted according to the effectiveness and tolerability for each individual patient.
Patients should be instructed to take SALAZOPYRIN EN-tabs in two equal doses, preferably after meals, and to swallow the tablets whole.
Ulcerative colitis
Initial therapy
Adults: 3-4 g/day in equal doses, with intervals between doses not exceeding 8 hours. It may be advisable to start therapy with lower doses, e.g. 1-2 g/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 in 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).
SALAZOPYRIN EN-tabs is particularly indicated for patients who cannot take uncoated sulfasalazine tablets due to gastrointestinal intolerance (e.g. loss of appetite, nausea). If symptoms of gastric intolerance (loss of appetite, nausea, vomiting, etc.) occur with the first few doses of SALAZOPYRIN EN-tabs, they are likely due to an increase in total serum sulfapyridine levels and can be reduced by halving the daily dose of SALAZOPYRIN EN-tabs and then gradually increasing it 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 SALAZOPYRIN EN-tabs, 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 SALAZOPYRIN EN-tabs 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 benefits are observed. The possibility of increasing the daily dose of the drug to 3 g may be considered if clinical efficacy after 12 weeks is insufficient. Careful monitoring of the patient's condition is recommended when using a dose of more than 2 g per day.
Recommended dosage regimen for rheumatoid arthritis in adults:
| Week | Number of tablets of the drug SALAZOPYRIN EN-tabs |
| treatment | In the morning | In the evening |
| 1 | - | One |
| 2 | One | One |
| 3 | One | Two |
| 4 | Two | Two |
Juvenile rheumatoid arthritis with polyarthritic syndrome
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).
Children aged 6 years and over: 30-50 mg/kg body weight per day, divided into 2 doses. Usually the maximum dose is 2 g per day. To reduce possible gastrointestinal intolerance, therapy should be initiated with a quarter or a third of the planned maintenance dose and increased weekly until the maintenance dose is reached after one 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 therapy with an initial total daily dose of 50–250 mg of sulfasalazine, doubling the dose every 4–7 days until the desired therapeutic level is achieved. If symptoms of sensitization recur, 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 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 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, convulsions, etc. Serum sulfapyridine concentrations can be used to monitor recovery from overdose.
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 kidney function, intensive hydration of the body is carried out. In the presence of oliguria, the amount of fluid and saline administered is limited and appropriate treatment is 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 contribute to their removal by dialysis.
Patients should be monitored for signs of methemoglobinemia or sulfhemoglobinemia and treated appropriately if these conditions are present.
Side effects
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. 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%), liver function test abnormalities (4%), leukopenia (3%), and thrombocytopenia (1%). There was one report of a 10% level of 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 SALAZOPYRIN EN-tabs.
Adverse reactions that occur infrequently or rarely
Infections and infestations: aseptic meningitis, pseudomembranous colitis.
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, epidermal necrolysis (Stevens-Johnson syndrome/toxic epidermal necrolysis) with corneal involvement, exfoliative dermatitis, 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
