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Delzicol

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Delzicol

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of mesalamine is unknown, but appears to be topical rather than systemic. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, that is, prostanoids, and through the lipoxygenase pathways, that is, leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with chronic ulcerative colitis, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon.

Pharmacokinetics

Absorption

Approximately 28 percent of mesalamine in mesalamine delayed-release formulations is absorbed after oral ingestion. The Tmax for mesalamine and its metabolite, is usually delayed, reflecting the delayed-release, and ranges from 4 to 16 hours.

The effect of food on the absorption of mesalamine from Delzicol has not been evaluated.

Metabolism

The absorbed mesalamine is rapidly acetylated in the gut mucosal wall and by the liver to N-acetyl-5aminosalicylic acid.

Excretion

Absorbed mesalamine is excreted mainly by the kidney as N-acetyl-5-aminosalicylic acid. Unabsorbed mesalamine is excreted in feces.

After intravenous administration, the elimination half-life of mesalamine is reported to be approximately 40 minutes. After oral dosing, the terminal t½ values for mesalamine and N-acetyl-5-aminosalicylic acid are usually about 12 hours, but are variable, ranging from 2 to 15 hours. There is a large inter-subject and intra-subject variability in the plasma concentrations of mesalamine and N-acetyl-5aminosalicylic acid and in their elimination half-lives following administration of Delzicol.

Animal Toxicology and/or Pharmacology

In animal studies (rats, mice, dogs), the kidney was the principal organ for toxicity. (In the following, comparisons of animal dosing to recommended human dosing are based on body surface area and a 2.4 g/day dose for a 60 kg person.)

Mesalamine causes renal papillary necrosis in rats at single doses of approximately 750 mg/kg to 1000 mg/kg (approximately 3 to 4 times the recommended human dose based on body surface area). Doses of 170 and 360 mg/kg/day (about 0.7 and 1.5 times the recommended human dose based on body surface area) given to rats for six months produced papillary necrosis, papillary edema, tubular degeneration, tubular mineralization, and urothelial hyperplasia.

In mice, oral doses of 4000 mg/kg/day mesalamine (approximately 8 times the recommended human dose based on body surface area) for three months produced tubular nephrosis, multifocal/diffuse tubulo-interstitial inflammation, and multifocal/diffuse papillary necrosis.

In dogs, single doses of 6000 mg (approximately 8 times the recommended human dose based on body surface area) of delayed-release mesalamine tablets resulted in renal papillary necrosis but were not fatal. Renal changes have occurred in dogs given chronic administration of mesalamine at doses of 80 mg/kg/day (1.1 times the recommended human dose based on body surface area).

Clinical Studies

The data presented in Section 14 are from clinical trials conducted with mesalamine delayed-release tablets. Delzicol is bioequivalent to these mesalamine delayed-release tablets.

Mildly to Moderately Active Ulcerative Colitis

Two placebo-controlled studies have demonstrated the efficacy of mesalamine delayed-release tablets in patients with mildly to moderately active ulcerative colitis. In one randomized, double-blind, multicenter trial of 158 patients, mesalamine delayed-release doses of 1.6 g/day and 2.4 g/day for 6 weeks were compared to placebo. The scoring system for determination of treatment efficacy included assessment of stool frequency, rectal bleeding, sigmoidoscopic findings, patient's functional assessment, and physician global assessment. At the dose of 2.4 g/day, 21 of 43 (49 percent) patients using mesalamine delayed-release tablets showed an improvement in sigmoidoscopic appearance of the bowel compared to 12 of 44 (27 percent) patients using placebo (p = 0.048). In addition, significantly more patients in mesalamine delayed-release tablets 2.4 g/day group showed improvement in rectal bleeding and stool frequency. The 1.6 g/day dose did not produce consistent evidence of effectiveness.

In a second randomized, double-blind, placebo-controlled clinical trial of 6 weeks duration in 87 patients, mesalamine delayed-release tablets, at a dose of 4.8 g/day, for 6 weeks, resulted in sigmoidoscopic improvement in 28 of 38 (74 percent) patients compared to 10 of 38 (26 percent) placebo patients (p < 0.001). Also, more patients in the mesalamine delayed-release tablets 4.8 g/day group showed improvement in overall symptoms.

Maintenance of Remission of Ulcerative Colitis

A 6-month, randomized, double-blind, placebo-controlled, multi-center study involved 264 patients treated with mesalamine delayed-release tablets 0.8 g/day (n = 90), 1.6 g/day (n = 87), or placebo (n = 87). In the 0.8g/day arm, patients were dosed twice daily; in the 1.6 g/day arm, patients were dosed four times daily. The proportion of patients treated with 0.8 g/day who maintained endoscopic remission was not statistically significant compared to placebo. The proportion of patients using mesalamine delayed-release tablets 1.6 g/day who maintained endoscopic remission of ulcerative colitis was in 61 of 87 (70.1 percent) compared with 42 of 87 (48.3 percent) of placebo patients (p = 0.005).

A pooled efficacy analysis of 4 maintenance trials compared mesalamine delayed-release tablets, at doses of 0.8 g/day to 2.8 g/day, in divided doses ranging from twice daily to four times per day, with sulfasalazine, at doses of 2 g/day to 4 g/day. Treatment success was seen in 59 of 98 (59 percent) patients using mesalamine delayed-release tablets and 70 of 102 (69 percent) of patients using sulfasalazine, a non-significant difference.

Last reviewed on RxList: 2/19/2013
This monograph has been modified to include the generic and brand name in many instances.

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