CONTRAINDICATIONS
Sulfasalazine Tablets Are Contraindicated In:
Hypersensitivity to sulfasalazine, its metabolites, sulfonamides or salicylates.
Pediatric patients under 2 years of age.
Patients with intestinal or urinary obstruction.
Patients with porphyria, as the sulfonamides have been reported to precipitate an acute
attack.
WARNINGS
Only after critical appraisal should sulfasalazine 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 sulfasalazine
tablets (see PRECAUTIONS, Laboratory Tests). Oligospermia and infertility have been observed
in men treated with sulfasalazine. Withdrawal of the drug appears to reverse these effects.
PRECAUTIONS
General
Sulfasalazine 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, sulfasalazine tablets should be discontinued immediately.
Additional Information for Delayed Release Tablets: Isolated instances have been reported
when sulfasalazine delayed release tablets have passed undisintegrated. If this is observed, the
administration of sulfasalazine delayed release tablets should be discontinued immediately.
Information for the Patient
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 sulfasalazine tablets in evenly divided doses, preferably after
meals, and to swallow the delayed release tablets whole. Additionally, patients should be advised
that sulfasalazine may produce an orange-yellow discoloration of the urine or skin.
Additional Information for Standard Release Tablets
They should also be made aware that ulcerative colitis rarely remits completely, and that the risk of
relapse can be substantially reduced by continued administration of sulfasalazine at a maintenance
dosage.
Additional Information for Delayed Release Tablets
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 sulfasalazine delayed release tablets at a maintenance dosage.
Rheumatoid Arthritis: Rheumatoid arthritis rarely remits. Therefore, continued administration of
sulfasalazine delayed release tablets 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 sulfasalazine tablets and every second week during the first 3 months of
therapy. During the second 3 months, the same tests should be done once monthly and, thereafter,
once every 3 months and as clinically indicated. Urinalysis and an assessment of renal function
should also be done periodically during treatment with sulfasalazine tablets.
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.
Drug/Laboratory Test Interactions
The presence of sulfasalazine or its metabolites in body fluids has not been reported to interfere
with laboratory test procedures.
Carcinogenesis, Mutagenesis, and 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, 2 (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) and 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.1
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.2 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.3
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 sulfasalazine tablets are 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 30-60% of those in the
maternal serum. Sulfapyridine has been shown to have a poor bilirubin-displacing capacity.
Pediatric Use
Standard Release Tablets: Safety and effectiveness in pediatric patients below the age of 2 years
have not been established.
Delayed Release Tablets: The safety and effectiveness of sulfasalazine delayed release tablets in
pediatric patients below the age of 2 years with ulcerative colitis have not been established. The
safety and effectiveness in juvenile rheumatoid arthritis have not been established. It has been
reported that the frequency of adverse events in patients with systemic onset of juvenile arthritis is
high.4