Mesalamine .375 g Capsule, Extended Release, 120-count — NDC 0832-6056-12 (Billing 00832-6056-12)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action The mechanism of action of mesalamine (5-ASA) is not fully understood, but appears to be a local anti-inflammatory effect on colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with ulcerative colitis, and it is possible that 5-ASA diminishes inflammation by blocking production of arachidonic acid metabolites.

12.3Pharmacokinetics Absorption The pharmacokinetics of 5-ASA and its metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), were studied after a single and multiple oral doses of 1.5 g mesalamine extended-release capsules in a crossover study in healthy subjects under fasting conditions. In the multiple-dose period, each subject received mesalamine extended-release capsules 1.5 g (four 0.375 g capsules) once daily for 7 consecutive days. Steady state was reached on Day 6 of once daily dosing based on trough concentrations.

After single and multiple doses of mesalamine extended-release capsules, peak plasma concentrations were observed at about 4 hours post-dose. At steady state, moderate increases (1.5-fold and 1.7-fold) in systemic exposure (AUC 0–24 ) to 5-ASA and N-Ac-5-ASA were observed when compared with a single-dose of mesalamine extended-release capsules. Pharmacokinetic parameters after a single dose of 1.5 g mesalamine extended-release capsules and at steady state in healthy subjects under fasting condition are shown in Table 2.

Table 2: Single Dose and Multiple Dose Mean (±SD) Plasma Pharmacokinetic Parameters of Mesalamine (5-ASA) and N-Ac-5-ASA After 1.5 g Mesalamine Extended-Release Capsules Administration in Healthy Subjects Mesalamine (5-ASA) Single Dose (n=24) Multiple Dose c (n=24) AUC 0–24 (mcg*h/mL) 11±5 17±6 AUC 0–inf (mcg*h/mL) 14±5 – C max (mcg/mL) 2.1±1.1 2.7±1.1 T max (h) a 4 (2, 16) 4 (2, 8) t ½ (h) b 9±7 10±8 N-Ac-5-ASA AUC 0–24 (mcg*h/mL) 26±6 37±9 AUC 0–inf (mcg*h/mL) 51±23 – C max (mcg/mL) 2.8±0.8 3.4±0.9 T max (h) a 4 (4, 12) 5 (2, 8) t ½ (h) b 12±11 14±10 a Median (range); b Harmonic mean (pseudo SD); c after 7 days of treatment In a separate study (n=30), it was observed that under fasting conditions about 32%±11% (mean±SD) of the administered dose was systemically absorbed based on the combined cumulative urinary excretion of 5-ASA and N-Ac-5-ASA over 96 hours post-dose.

Food Effects The effect of a high fat meal intake on absorption of mesalamine granules (the same granules contained in mesalamine extended-release capsules) was evaluated in 30 healthy subjects. Subjects received 1.6 g of mesalamine granules in sachet (2×0.8 g) following an overnight fast or a high fat meal in a crossover study. Under fed conditions, T max for both 5-ASA and N-Ac-5-ASA was prolonged by 4 and 2 hours, respectively.

A high fat meal did not affect C max for 5-ASA, but a 27% increase in the cumulative urinary excretion of 5-ASA was observed with a high fat meal. The overall extent of absorption of N-Ac-5-ASA was not affected by a high fat meal [see Dosage and Administration (2) ] . Distribution In an in vitro study, at 2.5 mcg/mL, mesalamine and N-Ac-5-ASA are 43±6% and 78±1% bound, respectively, to plasma proteins.

Protein binding of N-Ac-5-ASA does not appear to be concentration dependent at concentrations ranging from 1 to 10 mcg/mL. Elimination Metabolism The major metabolite of mesalamine is N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). It is formed by N-acetyltransferase activity in the liver and intestinal mucosa.

Excretion Following single and multiple doses of mesalamine extended-release capsules, the mean half-lives were 9 to 10 hours for 5-ASA, and 12 to 14 hours for N-Ac-5-ASA. Of the approximately 32% of the dose absorbed, about 2% of the dose was excreted unchanged in the urine, compared with about 30% of the dose excreted as N-Ac-5-ASA. Dru… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action The mechanism of action of mesalamine (5-ASA) is not fully understood, but appears to be a local anti-inflammatory effect on colonic epithelial cells. Mucosal production of arachidonic acid metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with ulcerative colitis, and it is possible that 5-ASA diminishes inflammation by blocking production of arachidonic acid metabolites.

12.3Pharmacokinetics Absorption The pharmacokinetics of 5-ASA and its metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), were studied after a single and multiple oral doses of 1.5 g mesalamine extended-release capsules in a crossover study in healthy subjects under fasting conditions. In the multiple-dose period, each subject received mesalamine extended-release capsules 1.5 g (four 0.375 g capsules) once daily for 7 consecutive days. Steady state was reached on Day 6 of once daily dosing based on trough concentrations.

After single and multiple doses of mesalamine extended-release capsules, peak plasma concentrations were observed at about 4 hours post-dose. At steady state, moderate increases (1.5-fold and 1.7-fold) in systemic exposure (AUC 0–24 ) to 5-ASA and N-Ac-5-ASA were observed when compared with a single-dose of mesalamine extended-release capsules. Pharmacokinetic parameters after a single dose of 1.5 g mesalamine extended-release capsules and at steady state in healthy subjects under fasting condition are shown in Table 2.

Table 2: Single Dose and Multiple Dose Mean (±SD) Plasma Pharmacokinetic Parameters of Mesalamine (5-ASA) and N-Ac-5-ASA After 1.5 g Mesalamine Extended-Release Capsules Administration in Healthy Subjects Mesalamine (5-ASA) Single Dose (n=24) Multiple Dose c (n=24) AUC 0–24 (mcg*h/mL) 11±5 17±6 AUC 0–inf (mcg*h/mL) 14±5 – C max (mcg/mL) 2.1±1.1 2.7±1.1 T max (h) a 4 (2, 16) 4 (2, 8) t ½ (h) b 9±7 10±8 N-Ac-5-ASA AUC 0–24 (mcg*h/mL) 26±6 37±9 AUC 0–inf (mcg*h/mL) 51±23 – C max (mcg/mL) 2.8±0.8 3.4±0.9 T max (h) a 4 (4, 12) 5 (2, 8) t ½ (h) b 12±11 14±10 a Median (range); b Harmonic mean (pseudo SD); c after 7 days of treatment In a separate study (n=30), it was observed that under fasting conditions about 32%±11% (mean±SD) of the administered dose was systemically absorbed based on the combined cumulative urinary excretion of 5-ASA and N-Ac-5-ASA over 96 hours post-dose.

Food Effects The effect of a high fat meal intake on absorption of mesalamine granules (the same granules contained in mesalamine extended-release capsules) was evaluated in 30 healthy subjects. Subjects received 1.6 g of mesalamine granules in sachet (2×0.8 g) following an overnight fast or a high fat meal in a crossover study. Under fed conditions, T max for both 5-ASA and N-Ac-5-ASA was prolonged by 4 and 2 hours, respectively.

A high fat meal did not affect C max for 5-ASA, but a 27% increase in the cumulative urinary excretion of 5-ASA was observed with a high fat meal. The overall extent of absorption of N-Ac-5-ASA was not affected by a high fat meal [see Dosage and Administration (2) ] . Distribution In an in vitro study, at 2.5 mcg/mL, mesalamine and N-Ac-5-ASA are 43±6% and 78±1% bound, respectively, to plasma proteins.

Protein binding of N-Ac-5-ASA does not appear to be concentration dependent at concentrations ranging from 1 to 10 mcg/mL. Elimination Metabolism The major metabolite of mesalamine is N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). It is formed by N-acetyltransferase activity in the liver and intestinal mucosa.

Excretion Following single and multiple doses of mesalamine extended-release capsules, the mean half-lives were 9 to 10 hours for 5-ASA, and 12 to 14 hours for N-Ac-5-ASA. Of the approximately 32% of the dose absorbed, about 2% of the dose was excreted unchanged in the urine, compared with about 30% of the dose excreted as N-Ac-5-ASA. Drug Interaction Studies In an in vitro study using human liver microsomes, 5-ASA and its metabolite, N-Ac-5-ASA, were shown not to inhibit the major CYP enzymes evaluated (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4).

Therefore, mesalamine and its metabolite are not expected to inhibit the metabolism of other drugs that are substrates of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4.

14 CLINICAL STUDIES Two similar, randomized, double-blind, placebo-controlled, multi-center studies were conducted in a total of 562 adult patients in remission from ulcerative colitis. The study populations had a mean age of 46 years (11% age 65 years or older), were 53% female, and were primarily white (92%). Ulcerative colitis disease activity was assessed using a modified Sutherland Disease Activity Index (DAI), which is a sum of four subscores based on stool frequency, rectal bleeding, mucosal appearance on endoscopy, and physician's rating of disease activity.

Each subscore can range from 0 to 3, for a total possible DAI score of 12. At baseline, approximately 80% of patients had a total DAI score of 0 or 1.0. Patients were randomized 2:1 to receive either mesalamine extended-release capsules 1.5 g or placebo once daily in the morning for six months.

Patients were assessed at baseline, 1 month, 3 months, and 6 months in the clinic, with endoscopy performed at baseline, at end of study, or if clinical symptoms developed. Relapse was defined as a rectal bleeding subscale score of 1 or more and a mucosal appearance subscale score of 2 or more using the DAI. The analysis of the intent-to-treat population was a comparison of the proportions of patients who remained relapse-free at the end of six months of treatment.

For the table below (Table 3) all patients who prematurely withdrew from the study for any reason were counted as relapses. In both studies, the proportion of patients who remained relapse-free at six months was greater for mesalamine extended-release capsules than for placebo. Table 3: Percentage of Ulcerative Colitis Patients Relapse-Free Relapse counted as rectal bleeding score ≥1 and mucosal appearance score ≥2, or premature withdrawal from study.

Through 6 Months in Mesalamine Extended-Release Capsules Maintenance Studies Mesalamine Extended-Release Capsules 1.5 g once daily % (# no relapse/N) Placebo % (# no relapse/N) Difference (95% C.I.) P-value Study 1 68% (143/209) 51% (49/96) 17% (5.5, 29.2) <0.001 Study 2 71% (117/164) 59% (55/93) 12% (0, 24.5) 0.046 Examination of gender subgroups did not identify difference in response to mesalamine extended-release capsules among these subgroups. There were too few elderly and too few African-American patients to adequately assess difference in effects in those populations.

The use of mesalamine extended-release capsules for treating ulcerative colitis beyond six months has not been evaluated in controlled clinical trials.

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Dietary mesalamine was not carcinogenic in rats at doses as high as 480 mg/kg/day, or in mice at 2,000 mg/kg/day. These doses are about 2.6 and 5.4 times the recommended human dose of granulated mesalamine capsules of 1.5 g/day (30 mg/kg if 50 kg body weight assumed or 1,110 mg/m 2 ), respectively, based on body surface area. Mesalamine was negative in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the sister chromatid exchange assay in the Chinese hamster bone marrow test, and the mouse bone marrow micronucleus test.

No effects on fertility or reproductive performance in male and female rats were observed with oral mesalamine doses up to 320 mg/kg (about 1.7 times the recommended human dose based on body surface area).

13.2Animal Toxicology and/or Pharmacology Renal Toxicity Animal studies with mesalamine (13-week and 26-week oral toxicity studies in rats, and 26-week and 52-week oral toxicity studies in dogs) have shown the kidney to be the major target organ of mesalamine toxicity. Single oral doses of 800 mg/kg (about 2.2 times the recommended human dose, on the basis of body surface area) and 1,800 mg/kg (about 9.7 times the recommended human dose, on the basis of body surface area) of mesalamine were lethal to mice and rats, respectively, and resulted in gastrointestinal and renal toxicity.

Oral doses of 40 mg/kg/day (about 0.20 times the human dose, on the basis of body surface area) produced minimal to slight tubular injury, and doses of 160 mg/kg/day (about 0.90 times the human dose, on the basis of body surface area) or higher in rats produced renal lesions including tubular degeneration, tubular mineralization, and papillary necrosis. Oral doses of 60 mg/kg/day (about 1.1 times the human dose, on the basis of body surface area) or higher in dogs also produced renal lesions including tubular atrophy, interstitial cell infiltration, chronic nephritis, and papillary necrosis.