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Asacol

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Asacol

Asacol

CLINICAL PHARMACOLOGY

Mesalamine is thought to be the major therapeutically active part of the sulfasalazine molecule in the treatment of ulcerative colitis. Sulfasalazine is converted to equimolar amounts of sulfapyridine and mesalamine by bacterial action in the colon. The usual oral dose of sulfasalazine for active ulcerative colitis is 3 to 4 grams daily in divided doses, which provides 1.2 to 1.6 grams of mesalamine to the colon.

The mechanism of action of mesalamine (and sulfasalazine) is unknown, but appears to be topical rather than systemic. Mucosal production of arachidonic acid (AA) metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes (LTs) and hydroxyeicosatetraenoic acids (HETEs), is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalamine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin (PG) production in the colon.

Pharmacokinetics

Asacol tablets are coated with an acrylic-based resin that delays release of mesalamine until it reaches the terminal ileum and beyond. This has been demonstrated in human studies conducted with radiological and serum markers. Approximately 28% of the mesalamine in Asacol (mesalamine delayed-release tablets) tablets is absorbed after oral ingestion, leaving the remainder available for topical action and excretion in the feces. Absorption of mesalamine is similar in fasted and fed subjects. The absorbed mesalamine is rapidly acetylated in the gut mucosal wall and by the liver. It is excreted mainly by the kidney as N-acetyl-5-aminosalicylic acid.

Mesalamine from orally administered Asacol tablets appears to be more extensively absorbed than the mesalamine released from sulfasalazine. Maximum plasma levels of mesalamine and N-acetyl-5-aminosalicylic acid following multiple Asacol (mesalamine delayed-release tablets) doses are about 1.5 to 2 times higher than those following an equivalent dose of mesalamine in the form of sulfasalazine. Combined mesalamine and N-acetyl-5-aminosalicylic acid AUC's and urine drug dose recoveries following multiple doses of Asacol (mesalamine delayed-release tablets) tablets are about 1.3 to 1.5 times higher than those following an equivalent dose of mesalamine in the form of sulfasalazine.

The tmax for mesalamine and its metabolite, N-acetyl-5-aminosalicylic acid, is usually delayed, reflecting the delayed release, and ranges from 4 to 12 hours. The half-lives of elimination (t½elm) 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 intersubject variability in the plasma concentrations of mesalamine and N-acetyl-5-aminosalicylic acid and in their elimination half-lives following administration of Asacol (mesalamine delayed-release tablets) tablets.

Clinical Studies

Mildly to moderately active ulcerative colitis

Two placebo-controlled studies have demonstrated the efficacy of Asacol (mesalamine delayed-release tablets) tablets in patients with mildly to moderately active ulcerative colitis. In one randomized, double-blind, multi-center trial of 158 patients, Asacol (mesalamine delayed-release tablets) doses of 1.6 g/day and 2.4 g/day were compared to placebo. At the dose of 2.4 g/day, Asacol (mesalamine delayed-release tablets) tablets reduced the disease activity, with 21 of 43 (49%) Asacol (mesalamine delayed-release tablets) patients showing improvement in sigmoidoscopic appearance of the bowel compared to 12 of 44 (27%) placebo patients (p = 0.048). In addition, significantly more patients in the Asacol (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 ulcerative colitis patients, Asacol (mesalamine delayed-release tablets) tablets, at a dose of 4.8 g/day, gave sigmoidoscopic improvement in 28 of 38 (74%) patients compared to 10 of 38 (26%) placebo patients (p < 0.001). Also, more patients in the Asacol (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 Asacol (mesalamine delayed-release tablets) 0.8 g/day (n = 90), 1.6 g/day (n = 87), or placebo (n = 87). The proportion of patients treated with 0.8 g/day who maintained endoscopic remission was not statistically significant compared to placebo. In the intention to treat (ITT) analysis of all 174 patients treated with Asacol (mesalamine delayed-release tablets) 1.6 g/day or placebo, Asacol (mesalamine delayed-release tablets) maintained endoscopic remission of ulcerative colitis in 61 of 87 (70.1%) of patients, compared to 42 of 87 (48.3%) of placebo recipients (p = 0.005).

A pooled efficacy analysis of 4 maintenance trials compared Asacol (mesalamine delayed-release tablets) , at doses of 0.8 g/day to 2.8 g/day, with sulfasalazine, at doses of 2 g/day to 4 g/day (n = 200). Treatment success was 59 of 98 (59%) for Asacol (mesalamine delayed-release tablets) and 70 of 102 (69%) for sulfasalazine, a non-significant difference.

Study to assess the effect on male fertility

The effect of Asacol (mesalamine) on sulfasalazine-induced impairment of male fertility was examined in an open-label study. Nine patients (age < 40 years) with chronic ulcerative colitis in clinical remission on sulfasalazine 2 g/day to 3 g/day were crossed over to an equivalent Asacol (mesalamine delayed-release tablets) dose (0.8 g/day to 1.2 g/day) for 3 months. Improvement in sperm count (p < 0.02) and morphology (p < 0.02) occurred in all cases. Improvement in sperm motility (p < 0.001) occurred in 8 of the 9 patients.

Last reviewed on RxList: 6/17/2010
This monograph has been modified to include the generic and brand name in many instances.

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