ulfasalazine; however, withdrawal of the drug appears to reverse these effects. serious infections serious infections, including fatal sepsis and pneumonia, have been reported. some infections were associated with agranulocytosis, neutropenia, or myelosuppression. discontinue sulfasalazine tablets if a patient develops a serious infection. closely monitor patients for the development of signs and symptoms of infection during and after treatment with sulfasalazine tablets. for a patient who develops a new infection during treatment with sulfasalazine tablets, perform a prompt and complete diagnostic workup for infection and myelosuppression. caution should be exercised when considering the use of sulfasalazine 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 reactions with eosinophilia and systemic symptoms (dress) severe, life-threatening, systemic hypersensitivity reactions such as drug reaction with eosinophilia and systemic symptoms (dress) have been reported in patients taking sulfasalazine. 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, evaluate the patient immediately. discontinue sulfasalazine tablets if an alternative etiology for the signs or symptoms cannot be established. other severe cutaneous adverse reactions other severe cutaneous adverse reactions, including exfoliative dermatitis, stevens-johnson syndrome (sjs) and toxic epidermal necrolysis (ten), and acute generalized exanthematous pustulosis (agep) have been reported in association with the use of sulfasalazine (see adverse reactions ). severe cutaneous adverse reactions can be serious and are sometimes fatal. patients are at highest risk for these events early in therapy, with most events occurring within the first month of treatment. discontinue sulfasalazine tablets at the first appearance of signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

doscopy 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 sulfasalazine 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 sulfasalazine, they are probably due to increased serum levels of total sulfapyridine and may be alleviated by halving the daily dose of sulfasalazine 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, sulfasalazine 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.

ocytic) 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 to report suspected adverse events, contact actavis at 1-888-838-2872 or fda at 1-800-fda-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

ey evaluated the outcome of pregnancies associated with inflammatory bowel disease (ibd). in a group of 186 women treated with sulfasalazine alone or sulfasalazine and concomitant steroid therapy, the incidence of fetal morbidity and mortality was comparable to that for 245 untreated ibd pregnancies as well as to pregnancies in the general population. 1 a study of 1,455 pregnancies associated with exposure to sulfonamides indicated that this group of drugs, including sulfasalazine, did not appear to be associated with fetal malformation. 2 a review of the medical literature covering 1,155 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. clinical considerations: sulfasalazine and its metabolite, sulfapyridine pass through the placenta. sulfasalazine and its metabolite are also present in human milk. in the newborn, sulfonamides compete with bilirubin for binding sites on the plasma proteins and may cause kernicterus. although sulfapyridine has been shown to have a poor bilirubin-displacing capacity, monitor the newborn for the potential for kernicterus. a case of agranulocytosis has been reported in an infant whose mother was taking both sulfasalazine and prednisone throughout pregnancy.

ell absorbed. absorption: following oral administration of 1 g of ssz to 9 healthy males, less than 15% of a dose of ssz is absorbed as parent drug. detectable serum concentrations of ssz have been found in healthy subjects within 90 minutes after the ingestion. maximum concentrations of ssz occur between 3 and 12 hours post-ingestion, with the mean peak concentration (6 mcg/ml) occurring at 6 hours. in comparison, peak plasma levels of both sp and 5-asa occur approximately 10 hours after dosing. this longer time to peak is indicative of gastrointestinal transit to the lower intestine where bacteria mediated metabolism occurs. sp apparently is well absorbed from the colon with an estimated bioavailability of 60%. in this same study, 5-asa is much less well absorbed from the gastrointestinal tract with an estimated bioavailability of from 10% to 30%. distribution: following intravenous injection, the calculated volume of distribution (vdss) for ssz was 7.5 ± 1.6 l. ssz is highly bound to albumin (>99.3%) while sp is only about 70% bound to albumin. acetylsulfapyridine (acsp), the principal metabolite of sp, is approximately 90% bound to plasma proteins. metabolism: as mentioned above, ssz is metabolized by intestinal bacteria to sp and 5-asa. approximately 15% of a dose of ssz is absorbed as parent and is metabolized to some extent in the liver to the same two species. the observed plasma half-life for intravenous sulfasalazine is 7.6 ± 3.4 hours. the primary route of metabolism of sp is via acetylation to form acsp. the rate of metabolism of sp to acsp is dependent upon acetylator phenotype. in fast acetylators, the mean plasma half-life of sp is 10.4 hours while in slow acetylators, it is 14.8 hours. sp can also be metabolized to 5-hydroxy-sulfapyridine (spoh) and n-acetyl-5-hydroxy-sulfapyridine. 5-asa is primarily metabolized in both the liver and intestine to n-acetyl-5-aminosalicylic acid via a non-acetylation phenotype dependent route. due to low plasma levels produced by 5-asa after oral administration, reliable estimates of plasma half-life are not possible. excretion: absorbed sp and 5-asa and their metabolites are primarily eliminated in the urine either as free metabolites or as glucuronide conjugates. the majority of 5-asa stays within the colonic lumen and is excreted as 5-asa and acetyl-5-asa with the feces. the calculated clearance of ssz following intravenous administration was 1 l/hr. renal clearance was estimated to account for 37% of total clearance. special populations elderly: elderly patients with rheumatoid arthritis showed a prolonged plasma half-life for ssz, sp, and their metabolites. the clinical impact of this is unknown. pediatric: small studies have been reported in the literature in children down to the age of 4 years with ulcerative colitis and inflammatory bowel disease. in these populations, relative to adults, the pharmacokinetics of ssz and sp correlated poorly with either age or dose. acetylator status: the metabolism of sp to acsp is mediated by polymorphic enzymes such that two distinct populations of slow and fast metabolizers exist. approximately 60% of the caucasian population can be classified as belonging to the slow acetylator phenotype. these subjects will display a prolonged plasma half-life for sp (14.8 hours vs 10.4 hours) and an accumulation of higher plasma levels of sp than fast acetylators. the clinical implication of this is unclear; however, in a small pharmacokinetic trial where acetylator status was determined, subjects who were slow acetylators of sp showed a higher incidence of adverse events. gender: gender appears not to have an effect on either the rate or the pattern of metabolites of ssz, sp, or 5-asa.

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/m 2 ). oligospermia and infertility have been described in men treated with sulfasalazine. withdrawal of the drug appears to reverse these effects.