ance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. if acute intolerance syndrome is suspected, promptly discontinue treatment with apriso. 5.3 hypersensitivity some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to apriso capsules or to other compounds that contain or are converted to mesalamine. 5.4 hepatic impairment there have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. caution should be exercised when administering apriso to patients with liver disease.

inical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. in the two placebo-controlled trials, 59% of apriso-treated patients experienced an adverse reaction compared with 64% of placebo patients. most adverse reactions with apriso were mild or moderate in severity. severe adverse reactions occurred in 6% of apriso-treated patients and 5% of placebo-treated patients. discontinuations due to adverse reactions occurred in 11% of apriso-treated patients and 17% of placebo-treated patients; the most common adverse reaction resulting in study discontinuation was recurrence of ulcerative colitis (apriso 6%, placebo 14%). the most common reactions reported with apriso (≥3%) are shown in table 1 below. table 1: treatment-emergent adverse reactions during clinical trials occurring in at least 3% of apriso-treated patients and at a greater rate than with placebo meddra preferred term apriso 1.5 g/day n=367 placebo n=185 headache 11% 8% diarrhea 8% 7% abdominal pain upper 5% 3% nausea 4% 3% nasopharyngitis 4% 3% influenza & influenza-like illness 4% 4% sinusitis 3% 3% the following adverse reactions, presented by body system, were reported at a frequency less than 3% in patients treated with apriso for up to 24 months in controlled and open-label trials. ear and labyrinth disorders : tinnitus, vertigo dermatological disorder : alopecia gastrointestinal : abdominal pain lower, rectal hemorrhage laboratory abnormalities : increased triglycerides, decreased hematocrit and hemoglobin general disorders and administration site disorders : fatigue hepatic : hepatitis cholestatic, transaminases increased renal disorders : creatinine clearance decreased, hematuria musculoskeletal : pain, arthralgia respiratory : dyspnea 6.2 adverse reaction information from other sources the following adverse reactions have been identified during clinical trials of a product similar to apriso and post approval use of other mesalamine-containing products such as apriso. because many of these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. body as a whole : lupus-like syndrome, drug fever cardiovascular : pericarditis, pericardial effusion, myocarditis gastrointestinal : pancreatitis, cholecystitis, gastritis, gastroenteritis, gastrointestinal bleeding, perforated peptic ulcer hepatic : jaundice, cholestatic jaundice, hepatitis, liver necrosis, liver failure, kawasaki-like syndrome including changes in liver enzymes hematologic : agranulocytosis, aplastic anemia nervous system : intracranial hypertension neurological/psychiatric : peripheral neuropathy, guillain-barré syndrome, transverse myelitis renal and urinary : nephrogenic diabetes insipidus respiratory/pulmonary : eosinophilic pneumonia, interstitial pneumonitis skin : psoriasis, pyoderma gangrenosum, erythema nodosum renal/urogenital : reversible oligospermia

esalamine and higher concentrations of its n-acetyl metabolite have been detected in human breast milk. the clinical significance of this has not been determined and there is limited experience of nursing women using mesalamine. caution should be exercised when apriso is administered to a nursing woman. 8.4 pediatric use safety and effectiveness of apriso capsules in pediatric patients have not been established. 8.5 geriatric use clinical studies of apriso did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. other reported clinical experience has not identified differences in responses between elderly and younger patients. in general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing apriso. reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia, pancytopenia, in patients who were 65 years or older who were taking mesalamine-containing products such as apriso. caution should be taken to closely monitor blood cell counts during mesalamine therapy. mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, care should be taken when prescribing this drug therapy [see warnings and precautions ( 5.1 )] .

h concentrations. after single and multiple doses of apriso, peak plasma concentrations were observed at about 4 hours post dose. at steady state, moderate increases (1.5-fold and 1.7-fold) in systemic exposure (auc 0-24 ) to 5-asa and n-ac-5-asa were observed when compared with a single-dose of apriso. pharmacokinetic parameters after a single dose of 1.5 g apriso and at steady state in healthy subjects under fasting condition are shown in table 2. table 2: single dose and multiple dose mean (±sd) plasma pharmacokinetic parameters of mesalamine (5-asa) and n-ac-5-asa after 1.5 g apriso administration in healthy subjects mesalamine (5-asa) single dose (n=24) multiple dose c (n=24) a median (range); b harmonic mean (pseudo sd); c after 7 days of treatment auc 0-24 (μg*h/ml) 11 ± 5 17 ± 6 auc 0-inf (μg*h/ml) 14 ± 5 - c max (μg/ml) 2.1 ± 1.1 2.7 ± 1.1 t max (h) a 4 (2, 16) 4 (2, 8) t ½ (h) b 9 ± 7 10 ± 8 n-ac-5-asa auc 0-24 (μg*h/ml) 26 ± 6 37 ± 9 auc 0-inf (μg*h/ml) 51 ± 23 - c max (μg/ml) 2.8 ± 0.8 3.4 ± 0.9 t max (h) a 4 (4, 12) 5 (2, 8) t ½ (h) b 12 ± 11 14 ± 10 in a separate study (n = 30), it was observed that under fasting conditions about 32% ± 11% (mean ± sd) of the administered dose was systemically absorbed based on the combined cumulative urinary excretion of 5-asa and n-ac-5-asa over 96 hours post-dose. the effect of a high fat meal intake on absorption of mesalamine granules (the same granules contained in apriso capsules) was evaluated in 30 healthy subjects. subjects received 1.6 g of mesalamine granules in sachet (2 x 0.8 g) following an overnight fast or a high fat meal in a crossover study. under fed conditions, t max for both 5-asa and n-ac-5-asa was prolonged by 4 and 2 hours, respectively. a high fat meal did not affect c max for 5-asa, but a 27% increase in the cumulative urinary excretion of 5-asa was observed with a high fat meal. the overall extent of absorption of n-ac-5-asa was not affected by a high fat meal. as apriso and mesalamine granules in sachet were bioequivalent, apriso can be taken without regard to food. distribution in an in vitro study, at 2.5 μg/ml, mesalamine and n-ac-5-asa are 43 ± 6% and 78 ± 1% bound, respectively, to plasma proteins. protein binding of n-ac-5-asa does not appear to be concentration dependent at concentrations ranging from 1 to 10 μg/ml. metabolism the major metabolite of mesalamine is n-acetyl-5-aminosalicylic acid (n-ac-5-asa). it is formed by n-acetyltransferase activity in the liver and intestinal mucosa. elimination following single and multiple doses of apriso, the mean half-lives were 9 to 10 hours for 5-asa, and 12 to 14 hours for n-ac-5-asa. of the approximately 32% of the dose absorbed, about 2% of the dose was excreted unchanged in the urine, compared with about 30% of the dose excreted as n-ac-5-asa. in vitro drug-drug interaction study in an in vitro study using human liver microsomes, 5-asa and its metabolite, n-ac-5-asa, were shown not to inhibit the major cyp enzymes evaluated (cyp1a2, cyp2c9, cyp2c19, cyp2d6, and cyp3a4). therefore, mesalamine and its metabolite are not expected to inhibit the metabolism of other drugs that are substrates of cyp1a2, cyp2c9, cyp2c19, cyp2d6, or cyp3a4.

esalamine (5-asa) and n-ac-5-asa after 1.5 g apriso administration in healthy subjects mesalamine (5-asa) single dose (n=24) multiple dose c (n=24) a median (range); b harmonic mean (pseudo sd); c after 7 days of treatment auc 0-24 (μg*h/ml) 11 ± 5 17 ± 6 auc 0-inf (μg*h/ml) 14 ± 5 - c max (μg/ml) 2.1 ± 1.1 2.7 ± 1.1 t max (h) a 4 (2, 16) 4 (2, 8) t ½ (h) b 9 ± 7 10 ± 8 n-ac-5-asa auc 0-24 (μg*h/ml) 26 ± 6 37 ± 9 auc 0-inf (μg*h/ml) 51 ± 23 - c max (μg/ml) 2.8 ± 0.8 3.4 ± 0.9 t max (h) a 4 (4, 12) 5 (2, 8) t ½ (h) b 12 ± 11 14 ± 10 in a separate study (n = 30), it was observed that under fasting conditions about 32% ± 11% (mean ± sd) of the administered dose was systemically absorbed based on the combined cumulative urinary excretion of 5-asa and n-ac-5-asa over 96 hours post-dose. the effect of a high fat meal intake on absorption of mesalamine granules (the same granules contained in apriso capsules) was evaluated in 30 healthy subjects. subjects received 1.6 g of mesalamine granules in sachet (2 x 0.8 g) following an overnight fast or a high fat meal in a crossover study. under fed conditions, t max for both 5-asa and n-ac-5-asa was prolonged by 4 and 2 hours, respectively. a high fat meal did not affect c max for 5-asa, but a 27% increase in the cumulative urinary excretion of 5-asa was observed with a high fat meal. the overall extent of absorption of n-ac-5-asa was not affected by a high fat meal. as apriso and mesalamine granules in sachet were bioequivalent, apriso can be taken without regard to food. distribution in an in vitro study, at 2.5 μg/ml, mesalamine and n-ac-5-asa are 43 ± 6% and 78 ± 1% bound, respectively, to plasma proteins. protein binding of n-ac-5-asa does not appear to be concentration dependent at concentrations ranging from 1 to 10 μg/ml. metabolism the major metabolite of mesalamine is n-acetyl-5-aminosalicylic acid (n-ac-5-asa). it is formed by n-acetyltransferase activity in the liver and intestinal mucosa. elimination following single and multiple doses of apriso, the mean half-lives were 9 to 10 hours for 5-asa, and 12 to 14 hours for n-ac-5-asa. of the approximately 32% of the dose absorbed, about 2% of the dose was excreted unchanged in the urine, compared with about 30% of the dose excreted as n-ac-5-asa. in vitro drug-drug interaction study in an in vitro study using human liver microsomes, 5-asa and its metabolite, n-ac-5-asa, were shown not to inhibit the major cyp enzymes evaluated (cyp1a2, cyp2c9, cyp2c19, cyp2d6, and cyp3a4). therefore, mesalamine and its metabolite are not expected to inhibit the metabolism of other drugs that are substrates of cyp1a2, cyp2c9, cyp2c19, cyp2d6, or cyp3a4.

icity studies in dogs) have shown the kidney to be the major target organ of mesalamine toxicity. oral doses of 40 mg/kg/day (about 0.20 times the human dose, on the basis of body surface area) produced minimal to slight tubular injury, and doses of 160 mg/kg/day (about 0.90 times the human dose, on the basis of body surface area) or higher in rats produced renal lesions including tubular degeneration, tubular mineralization, and papillary necrosis. oral doses of 60 mg/kg/day (about 1.1 times the human dose, on the basis of body surface area) or higher in dogs also produced renal lesions including tubular atrophy, interstitial cell infiltration, chronic nephritis, and papillary necrosis. overdosage single oral doses of 800 mg/kg (about 2.2 times the recommended human dose, on the basis of body surface area) and 1800 mg/kg (about 9.7 times the recommended human dose, on the basis of body surface area) of mesalamine were lethal to mice and rats, respectively, and resulted in gastrointestinal and renal toxicity.

study, or if clinical symptoms developed. relapse was defined as a rectal bleeding subscale score of 1 or more and a mucosal appearance subscale score of 2 or more using the dai. the analysis of the intent-to-treat population was a comparison of the proportions of patients who remained relapse-free at the end of six months of treatment. for the table below (table 3) all patients who prematurely withdrew from the study for any reason were counted as relapses. in both studies, the proportion of patients who remained relapse-free at six months was greater for apriso than for placebo. table 3: percentage of patients relapse-free* through 6 months in apriso maintenance studies apriso 1.5 g/day % (# no relapse/n) placebo % (# no relapse/n) difference (95% c.i.) p-value *relapse counted as rectal bleeding score ≥ 1 and mucosal appearance score ≥ 2, or premature withdrawal from study. study 1 68% (143/209) 51% (49/96) 17% (5.5, 29.2) <0.001 study 2 71% (117/164) 59% (55/93) 12% (0, 24.5) 0.046 examination of gender subgroups did not identify difference in response to apriso among these subgroups. there were too few elderly and too few african-american patients to adequately assess difference in effects in those populations. the use of apriso for treating ulcerative colitis beyond six months has not been evaluated in controlled clinical trials.

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