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Mechanism of Action
The mechanism of action of mesalamine is not fully understood, but appears to be topical rather than systemic. Although the pathology of inflammatory bowel disease is uncertain, both prostaglandins and leukotrienes have been implicated as mediators of mucosal injury and inflammation.
Mesalamine (5-ASA) administered as a rectal suppository is variably absorbed. In patients with ulcerative colitis treated with mesalamine 500 mg rectal suppositories, administered once every eight hours for six days, the mean mesalamine peak plasma concentration (Cmax) was 353 ng/mL (CV=55%) following the initial dose and 361 ng/mL (CV=67%) at steady state. The mean minimum steady state plasma concentration (Cmin) was 89 ng/mL (CV=89%). Absorbed mesalamine does not accumulate in the plasma.
Mesalamine administered as rectal suppositories distributes in rectal tissue to some extent. In patients with ulcerative proctitis treated with CANASA 1000 mg rectal suppositories, rectal tissue concentrations for 5-ASA and N-acetyl-5-ASA have not been rigorously quantified.
Mesalamine is extensively metabolized, mainly to Nacetyl-5-ASA. The site of metabolism has not been elucidated. In patients with ulcerative colitis treated with one 500 mg mesalamine rectal suppository every eight hours for six days, peak concentration (Cmax) of N-acetyl-5-ASA ranged from 467 ng/mL to 1399 ng/mL following the initial dose and from 193 ng/mL to 1304 ng/mL at steady state.
Mesalamine is eliminated from plasma mainly by urinary excretion, predominantly as N-acetyl-5-ASA. In patients with ulcerative proctitis treated with one mesalamine 500 mg rectal suppository every eight hours for six days, ≤ 12% of the dose was eliminated in urine as unchanged 5ASA and 8-77% as N-acetyl-5-ASA following the initial dose. At steady state, ≤ 11% of the dose was eliminated as unchanged 5-ASA and 3-35% as Nacetyl-5-ASA. The mean elimination half-life was five hours (CV=73%) for 5-ASA and six hours (CV=63%) for N-acetyl-5-ASA following the initial dose. At steady state, the mean elimination half-life was seven hours for both 5-ASA and N-acetyl-5-ASA (CV=102% for 5-ASA and 82% for N-acetyl-5ASA).
Animal Toxicology and/or Pharmacology
Toxicology studies of mesalamine were conducted in rats, mice, rabbits and dogs, and the kidney was the main target organ of toxicity. In rats, adverse renal effects were observed at a single oral dose of 600 mg/kg (about 3.2 times the recommended human intra-rectal dose, based on body surface area) and at IV doses of > 214 mg/kg (about 1.2 times the recommended human intra-rectal dose, based on body surface area). In a 13-week oral gavage toxicity study in rats, papillary necrosis and/or multifocal tubular injury were observed in males receiving 160 mg/kg (about 0.86 times the recommended human intra-rectal dose, based on body surface area) and in both males and females at 640 mg/kg (about 3.5 times the recommended human intra-rectal dose, based on body surface area). In a combined 52-week toxicity and 127-week carcinogenicity study in rats, degeneration of the kidneys and hyalinization of basement membranes and Bowman's capsule were observed at oral doses of 100 mg/kg/day (about 0.54 times the recommended human intra-rectal dose, based on body surface area) and above. In a 14-day rectal toxicity study of mesalamine suppositories in rabbits, intra-rectal doses up to 800 mg/kg (about 8.6 times the recommended human intra-rectal dose, based on body surface area) was not associated with any adverse effects. In a six-month oral toxicity study in dogs, doses of 80 mg/kg (about 1.4 times the recommended human intra-rectal dose, based on body surface area) and higher caused renal pathology similar to that described for the rat. In a rectal toxicity study of mesalamine suppositories in dogs, a dose of 166.6 mg/kg (about 3.0 times the recommended human intra-rectal dose, based on body surface area) produced chronic nephritis and pyelitis. In the 12-month eye toxicity study in dogs, keratoconjunctivitis sicca (KCS) occurred at oral doses of 40 mg/kg (about 0.72 times the recommended human intra-rectal dose, based on body surface area) and above.
Two double-blind, placebo-controlled, multicenter studies were conducted in North America in patients with mild to moderate active ulcerative proctitis. The primary measures of efficacy were the same in both trials (clinical disease activity index (DAI) and histologic evaluations). The DAI is a composite index reflecting rectal bleeding, stool frequency, mucosal appearance at endoscopy, and a physician's global assessment of disease. The main difference between the studies was dosage regimen: 500 mg three times daily (1.5 g/d) in Study 1; and 500 mg twice daily (1.0 g/d) in Study 2. A total of 173 patients were studied (Study 1, N=79; Study 2, N=94). Eighty-nine (89) patients received mesalamine suppositories, and eighty-four (84) patients received placebo suppositories. Patients were evaluated clinically and sigmoidoscopically after three and six weeks of suppository treatment. In Study 1, patients were 17 to 73 years of age (mean = 39 years), 57% were female, and 97% were white. Patients had an average extent of proctitis (upper disease boundary) of 10.8 cm. Eighty-four percent (84%) of the study patients had multiple prior episodes of proctitis. In Study 2, patients were 21 to 72 years of age (mean = 39 years), 62% were female, and 96% were white. Patients had an average extent of proctitis (upper disease boundary) of 10.3 cm. Seventy-eight percent (78%) of the study patients had multiple prior episodes of proctitis.
Compared to placebo, mesalamine suppository treatment was statistically (p < 0.01) superior to placebo in both trials with respect to improvement in stool frequency, rectal bleeding, mucosal appearance, disease severity, and overall disease activity at three and six weeks of treatment. The effectiveness of mesalamine suppositories was statistically significant irrespective of sex, extent of proctitis, duration of current episode, or duration of disease.
An additional multicenter, open-label, randomized, parallel group study in ninety-nine (99) patients diagnosed with mild to moderate ulcerative proctitis compared the clinical efficacy of the CANASA 1000 mg suppository to that of the CANASA 500 mg suppository. The primary measures of efficacy included the clinical disease activity index (DAI) and histologic evaluations. Patients were randomized to one of two treatment groups, with a dosage regimen of one 500 mg mesalamine suppository twice daily, morning and at bedtime, or one 1000 mg mesalamine suppository at bedtime for 6 weeks. Patients were evaluated clinically and sigmoidoscopically at three and six weeks of suppository treatment. Of the eighty-one (81) patients in the Per Protocol population, forty-six (46) patients received mesalamine 500 mg suppositories twice daily, and thirty-five (35) patients received mesalamine 1000 mg suppositories at bedtime.
The efficacy of the 1000 mg at bedtime treatment was not different at 6 weeks from the 500 mg twice daily treatment, and both were effective in the treatment of ulcerative proctitis. Both treatments resulted in a significant decrease at 6 weeks in DAI. In the 500 mg twice daily group, the mean DAI value decreased from 6.6 to 1.6, and in the 1000 mg at bedtime group, the mean DAI value decreased from 6.2 to 1.3 over 6 weeks of treatment, representing a decrease of greater than 75% in both groups. Seventy-eight percent (78%; 36/46) of patients in the 500 mg twice daily group and 86% (30/35) of the patients in the 1000 mg at bedtime group achieved a DAI score of less than 3 after 6 weeks of treatment.
Last reviewed on RxList: 2/26/2013
This monograph has been modified to include the generic and brand name in many instances.
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