MESALAMINE (Page 3 of 4)

10 OVERDOSAGE

Mesalamine is an aminosalicylate, and symptoms of salicylate toxicity include nausea, vomiting and abdominal pain, tachypnea, hyperpnea, tinnitus, and neurologic symptoms (headache, dizziness, confusion, seizures). Severe salicylate intoxication may lead to electrolyte and blood pH imbalance and potentially to other organ (e.g., renal and liver) damage. There is no specific antidote for mesalamine overdose; however, conventional therapy for salicylate toxicity may be beneficial in the event of acute overdosage and may include gastrointestinal tract decontamination to prevent further absorption. Correct fluid and electrolyte imbalance by the administration of appropriate intravenous therapy and maintain adequate renal function. Mesalamine is a pH-dependent delayed-release product and this factor should be considered when treating a suspected overdose.

11 DESCRIPTION

Each mesalamine capsule is a delayed- and extended-release dosage form for oral administration. Each capsule contains 0.375 g of mesalamine, USP (5-aminosalicylic acid, 5-ASA), an aminosalicylate. The structural formula of mesalamine is:

structure

Molecular Weight: 153.14

Molecular Formula: C7 H7 NO3

Each mesalamine extended-release capsule contains granules composed of mesalamine in a polymer matrix with an enteric coating that dissolves at pH 6 and above.

The inactive ingredients of mesalamine extended-release capsules are: microcrystalline cellulose, hypromellose, colloidal silicon dioxide, ethyl acrylate and methyl methacrylate 2:1 copolymer, magnesium stearate, methacrylic acid and methyl methacrylate 1:1 copolymer, talc, triethyl citrate, titanium dioxide and hypromellose phthalate.

The capsule shell contains titanium dioxide, FD&C Blue 1, FD&C Red 40 and gelatin. The capsule shells are printed with edible black ink containing shellac, black iron oxide and potassium hydroxide.

FDA approved dissolution test specifications differ from USP.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism 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.

12.3 Pharmacokinetics

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 in a crossover study in healthy subjects under fasting conditions. In the multiple-dose period, each subject received mesalamine 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, 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 (AUC0-24 ) to 5-ASA and N-Ac-5-ASA were observed when compared with a single-dose of mesalamine.

Pharmacokinetic parameters after a single dose of 1.5 g mesalamine 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 Administration in Healthy Subjects

Mesalamine (5-ASA) Single Dose (n=24) Multiple Dosec (n=24)
AUC0-24 (mcg*h/mL) AUC0-inf (mcg*h/mL) Cmax (mcg/mL) Tmax (h)a t½ (h)b 11±5 14±5 2.1±1.1 4 (2, 16) 9±7 17±6 — 2.7±1.1 4 (2, 8) 10±8
N-Ac-5-ASA
AUC0-24 (mcg*h/mL) AUC0-inf (mcg*h/mL) Cmax (mcg/mL) Tmax (h)a t½ (h)b 26±6 51±23 2.8±0.8 4 (4, 12) 12±11 37±9 — 3.4±0.9 5 (2, 8) 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 x 0.8 g) following an overnight fast or a high fat meal in a crossover study. Under fed conditions, Tmax for both 5-ASA and N-Ac-5-ASA was prolonged by 4 and 2 hours, respectively. A high fat meal did not affect Cmax 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, 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Dietary mesalamine was not carcinogenic in rats at doses as high as 480 mg/kg/day, or in mice at 2000 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 1110 mg/m2), 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).

13.2 Animal 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 1800 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.

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