Azulfidine (Sulfasalazine) EN-tabs Tablets contain sulfasalazine, formulated in a delayed release tablet (enteric-coated), 500 mg, for oral administration.

Azulfidine (Sulfasalazine) EN-tabs Tablets are film coated with cellulose acetate phthalate to retard disintegration of the tablet in the stomach and reduce potential irritation of the gastric mucosa.

Azulfidine (Sulfasalazine) EN-tabs Tablets are indicated:

Azulfidine (Sulfasalazine) EN-tabs is particularly indicated in patients with ulcerative colitis who cannot take uncoated sulfasalazine tablets because of gastrointestinal intolerance, and in whom there is evidence that this intolerance is not primarily the result of high blood levels of sulfapyridine and its metabolites, e.g., patients experiencing nausea and vomiting with the first few doses of the drug, or patients in whom a reduction in dosage does not alleviate the adverse gastrointestinal effects.

In patients with rheumatoid arthritis or juvenile rheumatoid arthritis, rest and physiotherapy as indicated should be continued. Unlike anti-inflammatory drugs, Azulfidine (Sulfasalazine) EN-tabs does not produce an immediate response. Concurrent treatment with analgesics and/or nonsteroidal anti-inflammatory drugs is recommended at least until the effect of Azulfidine (Sulfasalazine) EN-tabs is apparent.

Azulfidine (Sulfasalazine) EN-tabs Tablets are contraindicated in:Hypersensitivity to sulfasalazine, its metabolites, sulfonamides or salicylates,Patients with intestinal or urinary obstruction,Patients with porphyria, as the sulfonamides have been reported to precipitate an acute attack.

Only after critical appraisal should Azulfidine (Sulfasalazine) 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 or hepatotoxicity. Complete blood counts, as well as urinalysis with careful microscopic examination, should be done frequently in patients receiving Azulfidine (Sulfasalazine) EN-tabs (see ). Discontinue treatment with sulfasalazine while awaiting the results of blood tests. Oligospermia and infertility have been observed in men treated with sulfasalazine; however, withdrawal of the drug appears to reverse these effects.

Azulfidine (Sulfasalazine) 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 (Sulfasalazine) EN-tabs should be discontinued immediately.

Isolated instances have been reported when Azulfidine (Sulfasalazine) EN-tabs Tablets have passed undisintegrated. If this is observed, the administration of Azulfidine (Sulfasalazine) EN-tabs should be discontinued immediately.

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 (Sulfasalazine) 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.

Complete blood counts, including differential white cell count and liver function tests, should be performed before starting Azulfidine (Sulfasalazine) 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 (Sulfasalazine) EN-tabs.

The determination of serum sulfapyridine levels may be useful since concentrations greater than 50 µg/mL appear to be associated with an increased incidence of adverse reactions.

Reduced absorption of folic acid and digoxin have been reported when those agents were administered concomitantly with sulfasalazine.

When daily doses of sulfasalazine 2 g and weekly doses of methotrexate 7.5 mg were coadministered to 15 rheumatoid arthritis patients in a drug-drug interaction study, the pharmacokinetic disposition of the drugs was not altered.

Daily doses of sulfasalazine 2 g (maximum 3 g) and weekly doses of methotrexate 7.5 mg (maximum 15 mg) were administered alone or in combination to 310 rheumatoid arthritis patients in two controlled 52-week clinical studies. The overall toxicity profile of the combination revealed an increased incidence of gastrointestinal adverse events, especially nausea, when compared to the incidence associated with either drug administered alone.

Two year oral carcinogenicity studies were conducted in male and female F344/N rats and B6C3F1 mice. Sulfasalazine was tested at 84 (496 mg/m), 168 (991 mg/m) and 337.5 (1991 mg/m) 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/m), 1350 (4050 mg/m) and 2700 (8100 mg/m) 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/m). Oligospermia and infertility have been described in men treated with sulfasalazine. Withdrawal of the drug appears to reverse these 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.

Caution should be exercised when Azulfidine (Sulfasalazine) 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.

There have been reports of bloody stools or diarrhea in infants who were breastfeeding from mothers on sulfasalazine. In cases where the outcome was reported, bloody stools or diarrhea resolved in the infant after discontinuation of sulfasalazine in the mother.

The safety and effectiveness of Azulfidine (Sulfasalazine) EN-tabs in pediatric patients below the age of two years with ulcerative colitis have not been established.

The safety and effectiveness of Azulfidine (Sulfasalazine) 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 arthritis (see ).

It has been reported that the frequency of adverse events in patients with systemic-course of juvenile arthritis is high. Use in children with systemic-course juvenile rheumatoid arthritis has frequently resulted in a serum sickness-like reaction. 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.

The most common adverse reactions associated with sulfasalazine in ulcerative colitis are anorexia, headache, nausea, vomiting, gastric distress, and apparently reversible oligospermia. These occur in about one-third of the patients. Less frequent adverse reactions are pruritus, urticaria, rash, fever, Heinz body anemia, hemolytic anemia and cyanosis, which may occur at a frequency of 1 in 30 patients or less. Experience suggests that with a daily dose of 4 g or more, or total serum sulfapyridine levels above 50 µg/mL, the incidence of adverse reactions tends to increase.

Similar adverse reactions are associated with sulfasalazine use in adult rheumatoid arthritis, although there was a greater incidence of some reactions. In rheumatoid arthritis studies, the following common adverse reactions were noted: nausea (19%), dyspepsia (13%), rash (13%), headache (9%), abdominal pain (8%), vomiting (8%), fever (5%), dizziness (4%), stomatitis (4%), pruritis (4%), abnormal liver function tests (4%), leukopenia (3%), and thrombocytopenia (1%). One report showed a 10% rate of immunoglobulin suppression, which was slowly reversible and rarely accompanied by clinical findings.

In general, the adverse reactions in juvenile rheumatoid arthritis patients are similar to those seen in patients with adult rheumatoid arthritis except for a high frequency of serum sickness-like syndrome in systemic-course juvenile rheumatoid arthritis (see ). One clinical trial showed an approximate 10% rate of immunoglobulin suppression.

Although the listing which follows includes a few adverse reactions which have not been reported with this specific drug, the pharmacological similarities among the sulfonamides require that each of these reactions be considered when Azulfidine (Sulfasalazine) EN-tabs is administered.

Less common or rare adverse reactions include:

The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides), and oral hypoglycemic agents. Goiter production, diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides.

Cross-sensitivity may exist with these agents. Rats appear to be especially susceptible to the goitrogenic effects of sulfonamides and long-term administration has produced thyroid malignancies in this species.

None reported.

There is evidence that the incidence and severity of toxicity following overdosage is directly related to the total serum sulfapyridine concentration. Symptoms of overdosage may include nausea, vomiting, gastric distress and abdominal pains. In more advanced cases, central nervous system symptoms such as drowsiness, convulsions, etc., may be observed. Serum sulfapyridine concentrations may be used to monitor the progress of recovery from overdosage.

There are no documented reports of deaths due to ingestion of large single doses of sulfasalazine. It has not been possible to determine the LD in laboratory animals such as mice, since the highest oral daily dose of sulfasalazine which can be given (12 g/kg) is not lethal. Doses of regular sulfasalazine tablets of 16 g per day have been given to patients without mortality.

The dosage of Azulfidine (Sulfasalazine) EN-tabs Tablets should be adjusted to each individual's response and tolerance.

Patients should be instructed to take Azulfidine (Sulfasalazine) EN-tabs in evenly divided doses, preferably after meals, and to swallow the tablets whole.

Azulfidine (Sulfasalazine) EN-tabs Tablets, 500 mg, are elliptical, gold-colored, film enteric-coated tablets, monogrammed "102" on one side and "KPh" on the other. They are available in the following package sizes:

  Bottles of 100            NDC 0013-0102-01  Bottles of 300            NDC 0013-0102-20

NDC 0013-0102-01