rative colitis trials. (pentasa comparison to placebo) event pentasa 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 pentasa 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 pentasa therapy. postmarketing reports the following events have been identified during post-approval use of the pentasa brand of 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).

�) and rabbits at doses of 800 mg/kg/day (6856 mg/m²) 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.

elease 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 pentasa 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 pentasa 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 pentasa 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 pentasa 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 pentasa 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 pentasa dose. n-acetyl-5-aminosalicylic acid was the primary compound excreted in the urine (19% to 30%) following pentasa dosing.

been seen with pentasa capsules during controlled clinical trials.

/day (n=95) 2 g/day (n=97) 4 g/day (n=85) 2 g/day (n=83) 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. pga 36% 59% p<0.05 vs placebo. 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 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. 12% 26% 24% 12% 27% 12%