Sulfasalazine has been used in the treatment of ulcerative colitis for over 55 years. It is split by bacterial action in the colon into sulfapyridine (SP) and mesalamine (5-ASA). It is thought that the mesalamine component only is therapeutically active in ulcerative colitis.

Mechanism of Action

The mechanism of action of mesalamine (and sulfasalazine) 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. Recently, however, the role of mesalamine as a free radical scavenger or inhibitor of tumor necrosis factor (TNF) has also been postulated.

Pharmacokinetics

Absorption: 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.

Distribution: Mesalamine administered as rectal suppositories distributes in rectal tissue to some extent. In patients with ulcerative proctitis treated with CANASA® (mesalamine, USP) 1000 mg rectal suppositories, rectal tissue concentrations for 5-ASA and N-acetyl- 5-ASA have not been rigorously quantified.

Metabolism: Mesalamine is extensively metabolized, mainly to N-acetyl-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.

Elimination: 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 5-ASA 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 N-acetyl-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-5-ASA).

Drug-Drug Interactions: The potential for interactions between mesalamine, administered as 1000 mg rectal suppositories, and other drugs has not been studied.

Special Populations (Patients with Renal or Hepatic Impairment): The effect of renal or hepatic impairment on elimination of mesalamine in ulcerative proctitis patients treated with mesalamine 1000 mg suppositories has not been studied.

Preclinical Toxicology

Preclinical studies of mesalamine were conducted in rats, mice, rabbits and dogs, and 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.

Clinical Studies

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