Onset of adverse effects generally occurs within a few days to 12 weeks following initiation of sulfasalazine therapy, especially if dosage exceeds 4 g daily.
Clinical experience to date indicates that the incidence of sulfasalazine-induced adverse effects in patients with ulcerative colitis generally is similar to that reported in patients with rheumatoid arthritis, although there is a greater incidence of some reactions.
The most frequent adverse effects associated with sulfasalazine therapy in patients with ulcerative colitis are anorexia, headache, nausea, vomiting, gastric distress, and apparently reversible oligospermia. Other adverse effects reported in patients with ulcerative colitis include pruritus, urticaria, rash, fever, Heinz body anemia, hemolytic anemia, and cyanosis.
Adverse effects reported in patients with rheumatoid arthritis receiving sulfasalazine include nausea, dyspepsia, headache, abdominal pain, vomiting, fever, dizziness, stomatitis, rash, pruritus, abnormal liver function test results, leukopenia, and thrombocytopenia; reversible immunoglobulin suppression, rarely accompanied by clinical findings, has been observed in sulfasalazine-treated patients with rheumatoid arthritis. It appears that there are no drug-induced adverse effects that are specific to patients with rheumatoid arthritis; however, rash occurs more frequently in patients with rheumatoid arthritis than in those with ulcerative colitis, occurring in 13 or 3.3% of patients with rheumatoid arthritis or ulcerative colitis, respectively.
An increased incidence of adverse effects has been reported in patients receiving sulfasalazine daily dosages of 4 g or more or those with serum total sulfapyridine concentrations exceeding 50 mcg/mL. The ability to acetylate sulfasalazine may influence the onset and severity of adverse effects. In one study, 86% of patients exhibiting adverse effects were slow acetylators of sulfapyridine.
Nausea, vomiting, gastric distress, and anorexia occur in 8-33% of patients receiving sulfasalazine. Diarrhea, bloody diarrhea, neutropenic enterocolitis, hepatitis, hepatic failure, and pancreatitis have also been reported with sulfasalazine or other sulfonamides.
GI symptoms occurring after the first few days of sulfasalazine therapy are probably secondary to high serum concentrations of total sulfapyridine and may be alleviated by halving the dose and gradually increasing it over several days. If symptoms persist, the drug should be discontinued for 5-7 days, and therapy reinstituted at a lower daily dosage.
There have been isolated reports of sulfasalazine delayed-release tablets passing intact through the GI tract of some patients, possibly because of a lack of intestinal esterases capable of disintegrating the enteric coating. The drug should be discontinued immediately in such patients.
Hypersensitivity reactions, including erythema multiforme (Stevens-Johnson syndrome), exfoliative dermatitis, epidermal necrolysis (Lyell's syndrome) with corneal damage, rash with eosinophilia and systemic symptoms (DRESS), anaphylaxis, serum sickness syndrome, interstitial lung disease, pneumonitis with or without eosinophilia, vasculitis, fibrosing alveolitis, pleuritis, pericarditis with or without tamponade, allergic myocarditis, polyarteritis nodosa, lupus erythematosus-like syndrome, hepatitis and hepatic necrosis with or without immune complexes, fulminant hepatitis sometimes leading to liver transplantation, parapsoriasis varioliformis aculta (Mucha-Haberman syndrome), rhabdomyolysis, photosensitization, arthralgia, periorbital edema, conjunctival and scleral injection, and alopecia, have been reported with sulfasalazine or other sulfonamides.
Sulfasalazine should be used with caution in patients with severe allergy or bronchial asthma.
If a hypersensitivity reaction occurs during sulfasalazine therapy, the drug should be discontinued immediately.
Desensitization to sulfasalazine has been used when reinstitution of sulfasalazine therapy is considered necessary in patients who have had a hypersensitivity reaction to the drug; however, desensitization should not be attempted in patients with a history of agranulocytosis, toxic epidermal necrolysis, fibrosing alveolitis, or anaphylactoid reaction while receiving sulfasalazine.
Specialized references should be consulted for specific information on desensitization procedures and dosage. Although various desensitization procedures have been reported to be effective, many regimens use an initial sulfasalazine dosage of 50-250 mg daily which is then doubled every 4-7 days until the desired therapeutic dosage is attained. If manifestations of sensitivity recur, the drug should be discontinued.
Other Adverse Effects
A few cases of pulmonary eosinophilia and at least one fatality from fibrosing alveolitis have been reported in patients receiving sulfasalazine.
Sulfasalazine may impart an orange-yellow color to alkaline urine and skin, and patients should be advised of this effect.
Precautions and Contraindications
Sulfasalazine shares the toxic potentials of the sulfonamides, and the usual precautions of sulfonamide therapy should be observed.
Sulfasalazine should be used in patients with hepatic or renal damage or with blood dyscrasias only after critical appraisal. Fatalities related to hypersensitivity reactions, blood dyscrasias (e.g., agranulocytosis, aplastic anemia), renal and liver damage, irreversible neuromuscular and CNS changes, and fibrosing alveolitis have been reported in patients receiving the drug.
The presence of clinical signs such as sore throat, fever, pallor, purpura, or jaundice may indicate myelosuppression, hemolysis, or hepatotoxicity.
Complete blood cell counts (CBCs), with differentials, and liver function tests should be performed prior to initiation of sulfasalazine therapy and every 2 weeks during the first 3 months of therapy. These tests should then be performed once monthly during the second 3 months of therapy and once every 3 months thereafter and as clinically indicated. In addition urinalysis (with microscopic examination) should be done frequently and other renal function tests should be evaluated periodically during sulfasalazine therapy. The drug can be discontinued while awaiting results of blood tests.
Adequate fluid intake must be maintained during sulfasalazine therapy to reduce the risk of crystalluria and stone formation.
Patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency should be monitored closely for signs of hemolytic anemia; this adverse effect frequently is dose related.
Sulfasalazine is contraindicated in individuals hypersensitive to sulfasalazine, its metabolites, sulfonamides, or salicylates. The drug also is contraindicated in individuals with intestinal or urinary tract obstruction or porphyria.
Safety and efficacy of sulfasalazine conventional or delayed-release tablets in children younger than 2 years of age with ulcerative colitis have not been established.
Safety and efficacy of sulfasalazine delayed-release tablets for the management of polyarticular course juvenile rheumatoid arthritis in children 6-16 years of age is supported by evidence from adequate and well-controlled studies in adults. Adverse effects observed in children receiving sulfasalazine for the management of juvenile rheumatoid arthritis generally are similar to those observed in adults with rheumatoid arthritis. However, sulfasalazine therapy is associated with a high frequency of serum sickness-like syndrome in children with systemic course juvenile rheumatoid arthritis. This syndrome, which frequently is severe, presents as fever, nausea, vomiting, headache, rash, and abnormalities in liver function test results. Therefore, use of sulfasalazine in patients with systemic course juvenile rheumatoid arthritis is notrecommended.
Sulfasalazine, given as an initial dosage of 25-40 mg/kg daily and increased to 50-75 mg/kg daily (maximum daily dosage of 4 g), has been used in a limited number of pediatric patients with Crohn's disease (i.e., mild ileal, ileocecal, ileocolonic, or colonic disease). Limited data from a retrospective comparative study indicate that efficacy in maintaining remission of Crohn's disease is similar in children receiving sulfasalazine to those receiving oral mesalamine delayed-release tablets. However, some patients preferred mesalamine to sulfasalazine because of ease and frequency of administration and better tolerance.
Prolonged plasma elimination half-lives of sulfasalazine, sulfapyridine, and their metabolites have been reported in geriatric patients with rheumatoid arthritis. The clinical importance of these effects are not known.
Mutagenicity and Carcinogenicity
In carcinogenicity studies evaluating sulfasalazine in rats and mice, an increased incidence of urinary bladder transitional cell papillomas was observed in male rats and transitional cell papilloma of the kidney was observed in some female rats. In addition, an increased incidence of hepatocellular adenoma or carcinoma was observed in male and female mice.
Sulfasalazine was not mutagenic in the Ames test or in a mouse lymphoma cell assay; however, the drug showed equivocal mutagenic response in some other tests, including the micronucleus assay of mouse and rat bone marrow and mouse peripheral red blood cell, and the sister chromatid exchange, chromosomal aberration, and micronucleus assays in human lymphocytes.
Pregnancy, Fertility, and Lactation
Reproduction studies in rats and rabbits using sulfasalazine dosages up to 6 times the usual human dosage have not revealed evidence of harm to the fetus.
Sulfasalazine has been used for the treatment of inflammatory bowel disease, including Crohn's disease and ulcerative colitis, during pregnancy. Although fetal abnormalities occasionally have been reported in infants born to women with inflammatory bowel disease who received sulfasalazine alone or combined with corticosteroids during pregnancy, most evidence indicates that sulfasalazine is not associated with a substantial risk of teratogenicity and that the potential benefits of therapy with the drug generally appear to outweigh the possible risks in pregnant women with this disease. Although most experience with the use of sulfasalazine in pregnancy has been in women with inflammatory bowel disease, safety of the drug in pregnant women with rheumatoid arthritis is not expected to differ from that in inflammatory bowel disease and sulfasalazine therapy generally can be continued in pregnant women with rheumatoid arthritis. Some clinicians consider sulfasalazine the disease-modifying antirheumatic drug (DMARD) of choice in women who are planning to become pregnant or who are pregnant.
The risk of sulfasalazine-induced kernicterus in neonates born to women who received the drug during the last trimester appears to be low. Agranulocytosis has been reported in an infant whose mother received sulfasalazine and corticosteroid therapy throughout pregnancy. The effect of the drug on subsequent growth development and functional maturation in children whose mothers received sulfasalazine during pregnancy has not been determined.
Because there are no adequate and controlled studies to date using sulfasalazine in pregnant women, the drug should be used during pregnancy only when clearly needed.
Impairment of male fertility was observed in reproduction studies in rats using sulfasalazine dosages of 800 mg/kg daily. Oligospermia, abnormal sperm forms, impaired sperm motility, and infertility have occurred in men receiving sulfasalazine; however, these effects appear to be reversible following discontinuance of the drug. These effects appear to be caused by effects of sulfapyridine, not 5-aminosalicylic acid (mesalamine), on sperm maturation.
Sulfasalazine should be used with caution in nursing women since sulfonamides are distributed into milk.