Mesalamine Delayed-Release Capsules

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

Approximately 28% 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. A high fat meal increased systemic exposure of mesalamine (geometric mean Cmax: ↑ 64%; AUC: ↑ 48%) and delayed the tmax by 3.3 hours compared to results in the fasted state. A majority (85-90 %) of subjects in the fed state had systemic exposures within the range noted in the fasted state, with the exception of a few that had much higher exposures due to unknown reasons. The observed differences in mesalamine exposure due to concomitant food intake are not considered to be clinically relevant at the total daily dose of 2.4 g/day. Therefore DELZICOL can be taken without regard to food.

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

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 terminal half-lives following administration of DELZICOL.

Specific Populations

The pediatric data presented in Section 12 are from clinical trials conducted with mesalamine delayed-release 400 mg tablets. DELZICOL is bioequivalent to these mesalamine delayed-release tablets.

In a PK study evaluating 30, 60 and 90 mg/kg/day doses of mesalamine delayed-release 400 mg tablets administered twice daily for four weeks, the mean Cavg values of mesalamine in pediatric ulcerative colitis patients ranged from approximately 400 ng/mL to 2100 ng/mL based on data from all dose levels.

In a study in pediatric ulcerative colitis patients (Study 3), mean plasma concentrations of mesalamine (based on sparse sampling) were 820 to 988 ng/mL at the low dose level (that is, 1.2, 2.0 or 2.4 g/day based on body weight strata of 17 to less than 33 kg, 33 to less than 54 kg, and 54 to 90 kg, respectively).

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.

Treatment Of Mildly To Moderately Active Ulcerative Colitis

Two placebo-controlled studies (Studies 1 and 2) have demonstrated the efficacy of mesalamine delayed-release tablets in patients with mildly to moderately active ulcerative colitis.

In one randomized, double-blind, multi-center trial of 158 patients (Study 1), 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%) patients using mesalamine delayed-release tablets showed an improvement in sigmoidoscopic appearance of the bowel compared to 12 of 44 (27%) 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 (Study 2) 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%) patients compared to 10 of 38 (26%) placebo patients (p less than 0.001). Also, more patients in the mesalamine delayed-release tablets 4.8 g/day group than the placebo group showed improvement in overall symptoms.

The 4.8 d/day dose is not an approved dosage for the treatment of mildly to moderately active ulcerative colitis.

The safety and effectiveness of mesalamine delayed-release 400 mg tablets in pediatric patients 5 to 17 years of age for treatment of mildly to moderately active ulcerative colitis are supported by evidence from adequate and well controlled studies of mesalamine delayed-release 400 mg tablets in adults and a single study in pediatric patients.

A randomized, double-blind, 6-week study of 2 dose levels of mesalamine delayed-release 400 mg tablets (Study 3) was conducted in 82 pediatric patients 5 to 17 years of age with mildly or moderately active ulcerative colitis. All patients were divided by weight category (17 to less than 33 kg, 33 to less than 54 kg, and 54 to 90 kg) and randomly assigned to receive a low dose (1.2, 2.0, and 2.4 g/day for the respective weight category) or a high dose (2.0, 3.6, and 4.8 g/day). Doses were administered every 12 hours.

The proportion of patients who achieved success based on the Truncated Mayo Score (TM-Mayo) (based on the stool frequency and rectal bleeding subscores of the Mayo Score) and based on the Pediatric Ulcerative Colitis Activity Index (PUCAI) (which included assessment of abdominal pain, rectal bleeding, stool consistency and frequency, presence of nocturnal bowel movement and level of activity) was measured after 6 weeks of treatment. Success based on TM-Mayo was defined as either partial response (improvement from baseline in stool frequency or rectal bleeding subscores with no worsening in the other) or complete response (both stool frequency and rectal bleeding subscores equal 0). Success based on PUCAI was defined as either partial response (PUCAI reduction of greater than or equal to 20 points from Baseline to Week 6 with Week 6 score greater than or equal to 10) or complete response (PUCAI less than 10 at Week 6).

There were 41 patients in the low dose group and 41 patients in the high dose group who received at least one dose of mesalamine delayed-release 400 mg tablets; 36 patients in each dose group completed the study. Patients were considered treatment failures if they did not achieve success or dropped out due to adverse reaction or lack of efficacy.

At Week 6, 73.2% of the patients in the low dose group, and 70.0% of the patients in the high dose group achieved success based on the TM-Mayo; 34.1% of the patients in the low dose group and 42.5% of the patients in the high dose group achieved complete response. At Week 6, 56.1% of the patients in the low dose group, and 55.0% of the patients in the high dose group achieved success based on the PUCAI; 46.3% of the patients in the low dose group and 42.5%of the patients in the high dose group achieved complete response.

The high dose was not more effective than the low dose and is not an approved dosage [see DOSAGE AND ADMINISTRATION].

Maintenance Of Remission Of Ulcerative Colitis

A 6-month, randomized, double-blind, placebo-controlled, multi-center study (Study 4) 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 0.8 g/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%) compared with 42 of 87 (48.3%) 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%) patients using mesalamine delayed-release tablets and 70 of 102 (69%) of patients using sulfasalazine, a nonsignificant difference.

• Ulcerative Colitis