ntrolled ulcerative colitis trials. (mesalamine comparison to placebo) event mesalamine n = 451 placebo n = 173 diarrhea 16 (3.5%) 13 (7.5%) headache 10 (2.2%) 6 (3.5%) nausea 14 (3.1%) ----- abdominal pain 5 (1.1%) 7 (4.0%) melena (bloody diarrhea) 4 (0.9%) 6 (3.5%) rash 6 (1.3%) 2 (1.2%) anorexia 5 (1.1%) 2 (1.2%) fever 4 (0.9%) 2 (1.2%) rectal urgency 1 (0.2%) 4 (2.3%) nausea and vomiting 5 (1.1%) ----- worsening of ulcerative colitis 2 (0.4%) 2 (1.2%) acne 1 (0.2%) 2 (1.2%) clinical laboratory measurements showed no significant abnormal trends for any test, including measurement of hematological, liver, and kidney function. the following adverse events, presented by body system, were reported infrequently (i.e., less than 1%) during domestic ulcerative colitis and crohn’s disease trials. in many cases, the relationship to mesalamine has not been established. gastrointestinal: abdominal distention, anorexia, constipation, duodenal ulcer, dysphagia, eructation, esophageal ulcer, fecal incontinence, ggtp increase, gi bleeding, increased alkaline phosphatase, ldh increase, mouth ulcer, oral moniliasis, pancreatitis, rectal bleeding, sgot increase, sgpt increase, stool abnormalities (color or texture change), thirst dermatological: acne, alopecia, dry skin, eczema, erythema nodosum, nail disorder, photosensitivity, pruritus, sweating, urticaria nervous system: depression, dizziness, insomnia, somnolence, paresthesia cardiovascular: palpitations, pericarditis, vasodilation other: albuminuria, amenorrhea, amylase increase, arthralgia, asthenia, breast pain, conjunctivitis, ecchymosis, edema, fever, hematuria, hypomenorrhea, kawasaki-like syndrome, leg cramps, lichen planus, lipase increase, malaise, menorrhagia, metrorrhagia, myalgia, pulmonary infiltrates, thrombocythemia, thrombocytopenia, urinary frequency one week after completion of an 8-week ulcerative colitis study, a 72-year-old male, with no previous history of pulmonary problems, developed dyspnea. the patient was subsequently diagnosed with interstitial pulmonary fibrosis without eosinophilia by one physician and bronchiolitis obliterans with organizing pneumonitis by a second physician. a causal relationship between this event and mesalamine therapy has not been established. published case reports and/or spontaneous postmarketing surveillance have described infrequent instances of pericarditis, fatal myocarditis, chest pain and t-wave abnormalities, hypersensitivity pneumonitis, pancreatitis, nephrotic syndrome, interstitial nephritis, hepatitis, aplastic anemia, pancytopenia, leukopenia, agranulocytosis, or anemia while receiving mesalamine therapy. anemia can be a part of the clinical presentation of inflammatory bowel disease. allergic reactions, which could involve eosinophilia, can be seen in connection with mesalamine therapy. postmarketing reports the following events have been identified during post-approval use of the 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: gastrointestinal: reports of hepatotoxicity, including elevated liver enzymes (sgot/ast, sgpt/alt, ggt, ldh, alkaline phosphatase, bilirubin), hepatitis, jaundice, cholestatic jaundice, cirrhosis, 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. other: anaphylactic reaction, sjs/ten, dress, agep, pleurisy/pleuritis, pneumonitis, granulocytopenia, systemic lupus erythematosus, lupus-like syndrome, acute renal failure, interstitial lung disease, hypersensitivity pneumonitis (including interstitial pneumonitis, allergic alveolitis, eosinophilic pneumonitis), chronic renal failure, nephrogenic diabetes insipidus, nephrolithiasis, intracranial hypertension, angioedema, and oligospermia (reversible).

uish from a flare of inflammatory bowel disease. symptoms include cramping, acute abdominal pain, bloody diarrhea, and sometimes fever, headache, and rash. monitor patients for worsening of these symptoms while on treatment. if acute intolerance syndrome is suspected, promptly discontinue treatment with mesalamine extended-release capsules. hypersensitivity reactions hypersensitivity reactions have been reported in patients taking sulfasalazine. some patients may have a similar reaction to mesalamine or to other compounds that contain or are converted to mesalamine. as with sulfasalazine, mesalamine-induced hypersensitivity reactions may present as internal organ involvement, including myocarditis, pericarditis, nephritis, hepatitis, pneumonitis, and hematologic abnormalities. evaluate patients immediately if signs or symptoms of a hypersensitivity reaction are present. discontinue mesalamine if an alternative etiology for the signs and symptoms cannot be established. hepatic failure there have been reports of hepatic failure in patients with pre-existing liver disease who have been administered other products containing mesalamine. evaluate the risks and benefits of using mesalamine in patients with known liver impairment. severe cutaneous adverse reactions severe cutaneous adverse reactions, such as stevens-johnson syndrome (sjs) and toxic epidermal necrolysis (ten), drug reaction with eosinophilia and systemic symptoms (dress), and acute generalized exanthematous pustulosis (agep) have been reported in with the use of mesalamine (see adverse reactions ). discontinue mesalamine at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. photosensitivity patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema have reported more severe photosensitivity reactions. advise patients to avoid sun exposure, wear protective clothing, and use a broad-spectrum sunscreen when outdoors. nephrolithiasis cases of nephrolithiasis have been reported with the use of mesalamine, including stones with 100% mesalamine content. mesalamine-containing stones are radiotransparent and undetectable by standard radiography or computed tomography (ct). ensure adequate hydration during treatment.

2 ) and rabbits at doses of 800 mg/kg/day (6856 mg/m 2 ) revealed no evidence of teratogenic effects or harm to the fetus due to mesalamine. the estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. nonteratogenic effects published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with ulcerative colitis. adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

lcellulose-coated, extended-release formulation of mesalamine designed to release therapeutic quantities of mesalamine throughout the gastrointestinal tract. based on urinary excretion data, 20% to 30% of the mesalamine in mesalamine extended-release capsules is absorbed. in contrast, when mesalamine is administered orally as an unformulated 1-g aqueous suspension, mesalamine is approximately 80% absorbed. plasma mesalamine concentration peaked at approximately 1 mcg/ml 3 hours following a 1-g mesalamine dose and declined in a biphasic manner. the literature describes a mean terminal half-life of 42 minutes for mesalamine following intravenous administration. because of the continuous release and absorption of mesalamine from mesalamine extended-release capsule throughout the gastrointestinal tract, the true elimination half-life cannot be determined after oral administration. n-acetyl-5-aminosalicylic acid, the major metabolite of mesalamine (5‑aminosalicylic acid), peaked at approximately 3 hours at 1.8 mcg/ml, and its concentration followed a biphasic decline. pharmacological activities of n-acetyl-5-aminosalicylic acid are unknown, and other metabolites have not been identified. oral mesalamine pharmacokinetics were nonlinear when mesalamine extended-release capsules were dosed from 250 mg to 1 g four times daily, with steady-state mesalamine plasma concentrations increasing about nine times, from 0.14 mcg/ml to 1.21 mcg/ml, suggesting saturable first-pass metabolism. n-acetyl-5-aminosalicylic acid pharmacokinetics were linear. elimination: about 130 mg free mesalamine was recovered in the feces following a single 1-g mesalamine dose, which was comparable to the 140 mg of mesalamine recovered from the molar equivalent sulfasalazine tablet dose of 2.5 g. elimination of free mesalamine and salicylates in feces increased proportionately with mesalamine dose. n-acetyl-5‑aminosalicylic acid was the primary compound excreted in the urine (19% to 30%) following mesalamine dosing. clinical trials in two randomized, double-blind, placebo-controlled, dose-response trials (uc-1 and uc-2) of 625 patients with active mild to moderate ulcerative colitis, mesalamine, at an oral dose of 4 g/day given 1 g four times daily, produced consistent improvement in prospectively identified primary efficacy parameters, pga, tx f, and si as shown in the table below. the 4-g dose of mesalamine also gave consistent improvement in secondary efficacy parameters, namely the frequency of trips to the toilet, stool consistency, rectal bleeding, abdominal/rectal pain, and urgency. the 4-g dose of mesalamine induced remission as assessed by endoscopic and symptomatic endpoints. in some patients, the 2-g dose of mesalamine was observed to improve efficacy parameters measured. however, the 2-g dose gave inconsistent results in primary efficacy parameters across the two adequate and well controlled trials. parameter evaluated clinical trial uc-1 clinical trial uc-2 pl (n = 90) mesalamine pl (n = 83) mesalamine 4 g/day (n = 95) 2 g/day (n = 97) 4 g/day (n = 85) 2 g/day (n = 83) pga 36% 59% * 57% * 31% 55% * 41% tx f 22% 9% * 18% 31% 9% * 17% * si -2.5 -5.0 * -4.3 * -1.6 -3.8 * -2.6 remission † 12% 26% * 24% * 12% 27% * 12% * p<0.05 vs placebo. pga: physician global assessment: proportion of patients with complete or marked improvement. tx f: treatment failure: proportion of patients developing severe or fulminant uc requiring steroid therapy or hospitalization or worsening of the disease at 7 days of therapy, or lack of significant improvement by 14 days of therapy. si: sigmoidoscopic index: an objective measure of disease activity rated by a standard (15-point) scale that includes mucosal vascular pattern, erythema, friability, granularity/ulcerations, and mucopus: improvement over baseline. † defined as complete resolution of symptoms plus improvement of endoscopic endpoints. to be considered in remission, patients had a “1” score for one of the endoscopic components (mucosal vascular pattern, erythema, granularity, or friability) and “0” for the others.

been seen with mesalamine during controlled clinical trials.

n = 83) mesalamine 4 g/day (n = 95) 2 g/day (n = 97) 4 g/day (n = 85) 2 g/day (n = 83) pga 36% 59% * 57% * 31% 55% * 41% tx f 22% 9% * 18% 31% 9% * 17% * si -2.5 -5.0 * -4.3 * -1.6 -3.8 * -2.6 remission † 12% 26% * 24% * 12% 27% * 12% * p<0.05 vs placebo. pga: physician global assessment: proportion of patients with complete or marked improvement. tx f: treatment failure: proportion of patients developing severe or fulminant uc requiring steroid therapy or hospitalization or worsening of the disease at 7 days of therapy, or lack of significant improvement by 14 days of therapy. si: sigmoidoscopic index: an objective measure of disease activity rated by a standard (15-point) scale that includes mucosal vascular pattern, erythema, friability, granularity/ulcerations, and mucopus: improvement over baseline. † defined as complete resolution of symptoms plus improvement of endoscopic endpoints. to be considered in remission, patients had a “1” score for one of the endoscopic components (mucosal vascular pattern, erythema, granularity, or friability) and “0” for the others.