AZULFIDINE

AZULFIDINE Tablets contain sulfasalazine, 500 mg, for oral administration. Therapeutic Classification : Anti-inflammatory agent. Chemical Designation : 5-([p-(2-pyridylsulfamoyl)phenyl]azo) salicylic acid. Chemical Structure: Molecular Formula: C 18 H 14 N 4 O 5 S Inactive ingredients: magnesium stearate, povidone, silica (colloidal anhydrous), starch (pregelatinized). Chemical Structure

AZULFIDINE Tablets are indicated: • in the treatment of mild to moderate ulcerative colitis, and as adjunctive therapy in severe ulcerative colitis; and • for the prolongation of the remission period between acute attacks of ulcerative colitis.

The dosage of AZULFIDINE Tablets should be adjusted to each individual's response and tolerance. Initial Therapy Adults: 3 to 4 g daily in evenly divided doses with dosage intervals not exceeding eight hours. In some cases, it is advisable to initiate therapy with a smaller dosage, e.g., 1 to 2 g daily, to reduce possible gastrointestinal intolerance. If daily doses exceeding 4 g are required to achieve desired effects, the increased risk of toxicity should be kept in mind. Children, six years of age and older: 40 to 60 mg/kg body weight in each 24-hour period, divided into 3 to 6 doses. Maintenance Therapy Adults: 2 g daily. Children, six years of age and older: 30 mg/kg body weight in each 24-hour period, divided into 4 doses. The response of acute ulcerative colitis to AZULFIDINE Tablets can be evaluated by clinical criteria, including the presence of fever, weight changes, and degree and frequency of diarrhea and bleeding, as well as by sigmoidoscopy and the evaluation of biopsy samples. It is often necessary to continue medication even when clinical symptoms, including diarrhea, have been controlled. When endoscopic examination confirms satisfactory improvement, the dosage of AZULFIDINE should be reduced to a maintenance level. If diarrhea recurs, the dosage should be increased to previously effective levels. If symptoms of gastric intolerance (anorexia, nausea, vomiting, etc.) occur after the first few doses of AZULFIDINE, they are probably due to increased serum levels of total sulfapyridine and may be alleviated by halving the daily dose of AZULFIDINE and subsequently increasing it gradually over several days. If gastric intolerance continues, the drug should be stopped for 5 to 7 days, then reintroduced at a lower daily dose. Some patients may be sensitive to treatment with sulfasalazine. Various desensitization-like regimens have been reported to be effective in 34 of 53 patients, 4 7 of 8 patients, 5 and 19 of 20 patients. 6 These regimens suggest starting with a total daily dose of 50 to 250 mg sulfasalazine initially, and doubling it every 4 to 7 days until the desired therapeutic level is achieved. If the symptoms of sensitivity recur, AZULFIDINE should be discontinued. Desensitization should not be attempted in patients who have a history of agranulocytosis, or who have experienced an anaphylactoid reaction while previously receiving sulfasalazine.

AZULFIDINE Tablets are contraindicated in: Patients with intestinal or urinary obstruction, Patients with porphyria as sulfonamides have been reported to precipitate an acute attack, Patients hypersensitive to sulfasalazine, its metabolites, sulfonamides, or salicylates.

The most common adverse reactions associated with sulfasalazine 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 skin rash, pruritus, urticaria, fever, Heinz body anemia, hemolytic anemia, and cyanosis, which may occur at a frequency of one in every thirty patients or less. Experience suggests that with a daily dosage of 4 g or more, or total serum sulfapyridine levels above 50 µg/mL, the incidence of adverse reactions tends to increase. 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 Tablets are administered. Less common or rare adverse reactions include: Blood dyscrasias: aplastic anemia, agranulocytosis, leukopenia, megaloblastic (macrocytic) anemia, purpura, thrombocytopenia, hypoprothrombinemia, methemoglobinemia, congenital neutropenia, and myelodysplastic syndrome. Hypersensitivity reactions: erythema multiforme, epidermal necrolysis (SJS/TEN) with corneal damage, exfoliative dermatitis, DRESS, anaphylaxis, serum sickness syndrome, interstitial lung disease, pneumonitis with or without eosinophilia, vasculitis, fibrosing alveolitis, pleurisy/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 acuta (Mucha-Haberman syndrome), rhabdomyolysis, photosensitization, arthralgia, periorbital edema, conjunctival and scleral injection, and alopecia. Gastrointestinal reactions: hepatitis, hepatic failure, pancreatitis, bloody diarrhea, impaired folic acid absorption, impaired digoxin absorption, stomatitis, diarrhea, abdominal pains, and neutropenic enterocolitis. Central nervous system reactions: transverse myelitis, convulsions, meningitis, transient lesions of the posterior spinal column, cauda equina syndrome, Guillian-Barre syndrome, peripheral neuropathy, mental depression, vertigo, hearing loss, insomnia, ataxia, hallucinations, tinnitus, and drowsiness. Renal reactions: toxic nephrosis with oliguria and anuria, nephritis, nephrotic syndrome, urinary tract infections, hematuria, crystalluria, proteinuria, and hemolytic-uremic syndrome. Other reactions: urine discoloration and skin discoloration. 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. Postmarketing Reports The following events have been identified during post-approval use of products which contain (or are metabolized to) mesalamine in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of seriousness, frequency of reporting, or potential causal connection to mesalamine: Blood dyscrasias: pseudomononucleosis Cardiac disorders: myocarditis Hepatobiliary disorders: reports of hepatotoxicity, including elevated liver function tests (SGOT/AST, SGPT/ALT, GGT, LDH, alkaline phosphatase, bilirubin), jaundice, cholestatic jaundice, cirrhosis, hepatitis cholestatic, cholestasis and possible hepatocellular damage including liver necrosis and liver failure. Some of these cases were fatal. One case of Kawasaki-like syndrome, which included hepatic function changes, was also reported. Immune system disorders: anaphylaxis Metabolism and nutrition system disorders: folate deficiency Renal and urinary disorders: nephrolithiasis Respiratory, thoracic and mediastinal disorders: oropharyngeal pain Skin and subcutaneous tissue disorders: angioedema, purpura, SJS/TEN, DRESS, and AGEP Vascular disorders: pallor

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