Azulfidine®

WARNINGS Hepatic, Renal, and Hematologic Toxicity or Other Conditions Only after critical appraisal should AZULFIDINE 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. AZULFIDINE should be discontinued and the patient evaluated if significant hematological or hepatic toxicity occurs. Oligospermia and Infertility Oligospermia and infertility have been observed in men treated with sulfasalazine; however, withdrawal of the drug appears to reverse these effects. Serious Infections Serious and fatal infections, including sepsis and pneumonia, have been reported. Some infections were associated with agranulocytosis, neutropenia, or myelosuppression. Discontinue AZULFIDINE if a patient develops a serious infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with AZULFIDINE. For a patient who develops a new infection during treatment with AZULFIDINE, perform a prompt and complete diagnostic workup for infection and myelosuppression. Caution should be exercised when considering the use of AZULFIDINE in patients with a history of recurring or chronic infections or with underlying conditions or concomitant drugs which may predispose patients to infections. Hypersensitivity Reactions Severe hypersensitivity reactions may include internal organ involvement, such as hepatitis, nephritis, myocarditis, mononucleosis-like syndrome (i.e., pseudomononucleosis), hematological abnormalities (including hematophagic histiocytosis), and/or pneumonitis including eosinophilic infiltration. Severe Cutaneous Adverse Reactions Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): DRESS has been reported with sulfasalazine. DRESS consists of a combination of three or more of the following: cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, lymphadenopathy and one or more systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis. DRESS is sometimes fatal. Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. AZULFIDINE should be discontinued if an alternative cause for the signs or symptoms cannot be established. Other Severe Cutaneous Adverse Reactions: Other severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), exfoliative dermatitis, and acute generalized exanthematous pustulosis (AGEP), have been reported in association with sulfasalazine. These conditions can be serious or life-threatening. Advise patients of the signs and symptoms of severe skin reactions and to discontinue AZULFIDINE at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity. Severe cutaneous adverse reactions typically occur within the first month of treatment. PRECAUTIONS General AZULFIDINE 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, the drug should be discontinued immediately. Information for Patients Patients should be informed of the possibility of adverse reactions 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 informed that ulcerative colitis rarely remits completely, and that the risk of relapse can be reduced by continued administration of AZULFIDINE at a maintenance dosage. Patients should be instructed to take AZULFIDINE in evenly divided doses preferably after meals. Additionally, patients should be made aware that sulfasalazine may produce an orange-yellow discoloration of the urine or skin. Laboratory Tests Complete blood counts, including differential white cell count, and liver function tests, should be performed before starting AZULFIDINE 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. 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. Drug Interactions Reduced absorption of folic acid and digoxin have been reported when those agents were administered concomitantly with sulfasalazine. Drug/Laboratory Test Interactions Several reports of possible interference with measurements, by liquid chromatography, of urinary normetanephrine causing a false-positive test result have been observed in patients exposed to sulfasalazine or its metabolite, mesalamine/mesalazine. Sulfasalazine or its metabolite, sulfapyridine, may interfere with ultraviolet absorbance, particularly at 340 nm, and may cause interference with some laboratory assays that use NAD(H) or NADP(H) to measure ultraviolet absorbance around this wavelength. Examples of such assays may include alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase-muscle/brain (CK-MB), ammonia, thyroxine or glucose. Erroneous laboratory results may be observed in patients receiving higher doses of sulfasalazine. 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, a statistically significant increase in the incidence of renal pelvic/ureter tumors was observed. For the mouse study, sulfasalazine was tested at 675 (2025 mg/m2), 1350 (4050 mg/m2), and 2700 (8100 mg/m2) mg/kg/day. A statistically significant increase in the incidence of hepatocellular adenoma or carcinoma (combined) was observed in male and female mice at the highest dose. Sulfasalazine did not show mutagenicity in the bacterial reverse mutation assay (Ames test) and in 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 There are no adequate and well-controlled studies of sulfasalazine in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 6 times the human maintenance dose of 2 g/day based on body surface area 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 case of agranulocytosis was reported in an infant whose mother was taking both sulfasalazine and prednisone throughout pregnancy. A national survey of pregnant women found no statistically significant increase in the prevalence of birth defects among offspring of women who reported using sulfasalazine during the first trimester compared with women who did not report using sulfasalazine during the first trimester. Clinical Considerations Sulfasalazine and its metabolite, sulfapyridine pass through the placenta. Sulfasalazine and its metabolite are also present in human milk. A case where a newborn infant whose mother was taking sulfasalazine developed agranulocytosis has been reported. Sulfonamides, including sulfasalazine, compete with bilirubin for binding sites on the plasma proteins and may thus cause kernicterus in the newborn. Appropriate monitoring is recommended for newborns whose mothers were taking sulfasalazine during pregnancy. Nursing Mothers Sulfonamides, including sulfasalazine, are present in human milk. Insignificant amounts of sulfasalazine have been found in milk, whereas levels of the active metabolite sulfapyridine in milk are about 30 to 60 percent of those in the maternal serum. Caution should be exercised when AZULFIDINE is administered to a nursing mother. There are reports with limited data of bloody stools or diarrhea in human milk-fed infants of mothers taking sulfasalazine. In cases where the outcome was reported, bloody stools or diarrhea resolved in the infant after discontinuation of sulfasalazine in the mother or discontinuation of breastfeeding. Due to limited data, a causal relationship cannot be confirmed. Human milk-fed infants of mothers taking AZULFIDINE should be monitored for signs and symptoms of diarrhea and/or bloody stools. Pediatric Use Safety and effectiveness in pediatric patients below the age of 2 years have not been established.