Warnings & Precautions

Only after critical appraisal should AZULFIDINE EN-tabs Tablets be given to patients with hepatic or renal damage or blood dyscrasias. Deaths associated with the administration of sulfasalazine have been reported from hypersensitivity reactions, agranulocytosis, aplastic anemia, other blood dyscrasias, renal and liver damage, irreversible neuromuscular and central nervous system changes, and fibrosing alveolitis. The presence of clinical signs such as sore throat, fever, pallor, purpura or jaundice may be indications of serious blood disorders. Complete blood counts, as well as urinalysis with careful microscopic examination, should be done frequently in patients receiving AZULFIDINE EN-tabs (see PRECAUTIONS, Laboratory Tests). Oligospermia and infertility have been observed in men treated with sulfasalazine; however, withdrawal of the drug appears to reverse these effects.

PRECAUTIONS
General
AZULFIDINE EN-tabs Tablets should be given with caution to patients with severe allergy or bronchial asthma. Adequate fluid intake must be maintained in order to prevent crystalluria and stone formation. Patients with glucose-6-phosphate dehydrogenase deficiency should be observed closely for signs of hemolytic anemia. This reaction is frequently dose related. If toxic or hypersensitivity reactions occur, AZULFIDINE EN-tabs should be discontinued immediately.
Isolated instances have been reported when AZULFIDINE EN-tabs Tablets have passed undisintegrated. If this is observed, the administration of AZULFIDINE EN-tabs should be discontinued immediately.Information for Patients
Patients should be informed of the possibility of adverse effects and of the need for careful medical supervision. The occurrence of sore throat, fever, pallor, purpura or jaundice may indicate a serious blood disorder. Should any of these occur, the patient should seek medical advice.
Patients should be instructed to take AZULFIDINE EN-tabs in evenly divided doses, preferably after meals, and to swallow the tablets whole. Additionally, patients should be advised that sulfasalazine may produce an orange-yellow discoloration of the urine or skin.
Ulcerative Colitis
Patients with ulcerative colitis should be made aware that ulcerative colitis rarely remits completely, and that the risk of relapse can be substantially reduced by continued administration of AZULFIDINE EN-tabs at a maintenance dosage.
Rheumatoid Arthritis
Rheumatoid arthritis rarely remits. Therefore, continued administration of AZULFIDINE EN-tabs is indicated. Patients requiring sulfasalazine should follow up with their physicians to determine the need for continued administration.
Laboratory Tests
Complete blood counts, including differential white cell count and liver function tests, should be performed before starting AZULFIDINE EN-tabs and every second week during the first three months of therapy. During the second three months, the same tests should be done once monthly and thereafter once every three months, and as clinically indicated. Urinalysis and an assessment of renal function should also be done periodically during treatment with AZULFIDINE EN-tabs.
The determination of serum sulfapyridine levels may be useful since concentrations greater than 50 mg/mL appear to be associated with an increased incidence of adverse reactions.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Two year oral carcinogenicity studies were conducted in male and female F344/N rats and B6C3F1 mice. Sulfasalazine was tested at 84 (496 mg/m2), 168 (991 mg/m2) and 337.5 (1991 mg/m2) mg/kg/day doses in rats. A statistically significant increase in the incidence of urinary bladder transitional cell papillomas was observed in male rats. In female rats, two (4%) of the 337.5 mg/kg rats had transitional cell papilloma of the kidney. The increased incidence of neoplasms in the urinary bladder and kidney of rats was also associated with an increase in the renal calculi formation and hyperplasia of transitional cell epithelium. For the mouse study, sulfasalazine was tested at 675 (2025 mg/m2), 1350 (4050 mg/m2) and 2700 (8100 mg/m2) mg/kg/day. The incidence of hepatocellular adenoma or carcinoma in male and female mice was significantly greater than the control at all doses tested.
Sulfasalazine did not show mutagenicity in the bacterial reverse mutation assay (Ames test) or in the L51784 mouse lymphoma cell assay at the HGPRT gene. However, sulfasalazine showed equivocal mutagenic response in the micronucleus assay of mouse and rat bone marrow and mouse peripheral RBC and in the sister chromatid exchange, chromosomal aberration, and micronucleus assays in lymphocytes obtained from humans.
Impairment of male fertility was observed in reproductive studies performed in rats at a dose of 800 mg/kg/day (4800 mg/m2). Oligospermia and infertility have been described in men treated with sulfasalazine. Withdrawal of the drug appears to reverse these effects.
Pregnancy
Teratogenic Effects: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits at doses up to 6 times the human dose and have revealed no evidence of impaired female fertility or harm to the fetus due to sulfasalazine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
A national survey evaluated the outcome of pregnancies associated with inflammatory bowel disease (IBD). In 186 pregnancies in women treated with sulfasalazine alone or sulfasalazine and concomitant steroid therapy, the incidence of fetal morbidity and mortality was comparable both to that of 245 untreated IBD pregnancies, and to pregnancies in the general population.2
A study of 1455 pregnancies associated with exposure to sulfonamides including sulfasalazine, indicated that this group of drugs did not appear to be associated with fetal malformation.3 A review of the medical literature covering 1155 pregnancies in women with ulcerative colitis suggested that the outcome was similar to that expected in the general population.4
No clinical studies have been performed to evaluate the effect of sulfasalazine on the growth development and functional maturation of children whose mothers received the drug during pregnancy.
Nonteratogenic Effects: Sulfasalazine and sulfapyridine pass the placental barrier. Although sulfapyridine has been shown to have poor bilirubin-displacing capacity, the potential for kernicterus in newborns should be kept in mind.
A case of agranulocytosis has been reported in an infant whose mother was taking both sulfasalazine and prednisone throughout pregnancy.
Nursing Mothers
Caution should be exercised when AZULFIDINE EN-tabs is administered to a nursing mother. Sulfonamides are excreted in the milk. In the newborn, they compete with bilirubin for binding sites on the plasma proteins and may cause kernicterus. Insignificant amounts of uncleaved sulfasalazine have been found in milk, whereas the sulfapyridine levels in milk are about 30% to 60% of those in the maternal serum. Sulfapyridine has been shown to have a poor bilirubin-displacing capacity.
Pediatric Use
The safety and effectiveness of AZULFIDINE EN-tabs in pediatric patients below the age of two years with ulcerative colitis have not been established.
The safety and effectiveness of AZULFIDINE EN-tabs for the treatment of the signs and symptoms of polyarticular-course juvenile rheumatoid arthritis in pediatric patients aged 6-16 years is supported by evidence from adequate and well-controlled studies in adult rheumatoid arthritis patients. The extrapolation from adults with rheumatoid arthritis to children with polyarticular-course juvenile rheumatoid arthritis is based on similarities in disease and response to therapy between these two patient populations. Published studies support the extrapolation of safety and effectiveness for sulfasalazine to polyarticular-course juvenile rheumatoid arthritis1,5 (see ADVERSE REACTIONS).
It has been reported that the frequency of adverse events in patients with systemic-course of juvenile arthritis is high.6 Use in children with systemic-course juvenile rheumatoid arthritis has frequently resulted in a serum sickness-like reaction.5 This reaction is often severe and presents as fever, nausea, vomiting, headache, rash, and abnormal liver function tests. Treatment of systemic-course juvenile rheumatoid arthritis with sulfasalazine is not recommended.
REFERENCES
1. van Rossum MAJ, et al. Sulfasalazine in the treatment of juvenile chronic arthritis: a randomized, double-blind, placebo-controlled, multicenter study. Arth Rheum 1998;41:808-816.
2. Mogadam M, et al. Pregnancy in inflammatory bowel disease: effect of sulfasalazine and corticosteroids on fetal outcome. Gastroenterology 1981;80:726.
3.Kaufman DW, editor. Birth defects and drugs during pregnancy. Littleton, MA: Publishing Sciences Group, Inc., 1977:296-313.
4.Jarnerot G. Fertility, sterility and pregnancy in chronic inflammatory bowel disease. Scand J Gastroenterol 1982;17:1-4.
5.Imundo LF, Jacobs JC. Sulfasalazine therapy for juvenile rheumatoid arthritis. J Rheumatol 1996;23:360-366.
6.Hertzberger-ten Cate R, Cats A. Toxicity of sulfasalazine in systemic juvenile chronic arthritis. Clin Exp Rheumatol 1991;9: 85-8.