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Asacol HD (Mesalamine) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Each Asacol HD delayed-release tablet for oral administration contains 800 mg of mesalamine, an aminosalicylate. Asacol HD delayed-release tablets have an outer protective coat consisting of a combination of acrylic based resins, Eudragit S (methacrylic acid copolymer B, NF) and Eudragit L (methacrylic acid copolymer A, NF). The inner coat consists of an acrylic based resin, Eudragit S, which dissolves at pH 7 or greater, releasing mesalamine in the terminal ileum and beyond for topical anti-inflammatory action in the colon. Mesalamine (also referred to as 5-aminosalicylic acid or 5-ASA) has the chemical name 5-amino-2-hydroxybenzoic acid; its structural formula is:

Inactive Ingredients: Each tablet contains colloidal silicon dioxide, dibutyl phthalate, edible black ink, ferric oxide red, ferric oxide yellow, lactose monohydrate, magnesium stearate, methacrylic acid copolymer B (Eudragit S), methacrylic acid copolymer A (Eudragit L), polyethylene glycol, povidone, sodium starch glycolate, and talc.

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism of action of mesalamine is unknown, but appears to be topical rather than systemic. Mucosal production of arachidonic acid (AA) metabolites, both through the cyclooxygenase pathways, that is, prostanoids, and through the lipoxygenase pathways, that is, 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

Plasma concentrations of mesalamine (5-aminosalicylic acid; 5-ASA) and its metabolite, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA) are highly variable following administration of Asacol HD tablets. The time to peak plasma concentration (tmax) is prolonged for mesalamine and N-Ac-5-ASA with the median values from various studies ranging from 10 to 16 hours, reflecting the delayed-release characteristics. Based on cumulative urinary recovery of mesalamine and N-Ac-5-ASA from single dose studies in healthy volunteers, approximately 20 percent of the orally administered mesalamine in Asacol HD tablets is systemically absorbed. The absorbed mesalamine is rapidly acetylated in the gut mucosal wall and by the liver to N-Ac-5-ASA which is excreted mainly by the kidney. The PK parameters following administration of 1600 mg three times daily in healthy subjects are shown in Table 2.

Table 2. Mean (± S.D.) PK parameters in healthy subjects following administration of two 800 mg tablets three times daily for 6 days (n = 16)

Mesalamine

N-Ac-5-ASA

AUCtau (mcg h/mL)

20 ± 14

25 ± 11

Cmax (mcg/mL)

5.0 ± 4.0

4.6 ± 2.5

t1/2 (h)

12.6 ± 10.9 1

23.6 ± 11.2 2

1 n = 11
2 n = 6

A high fat meal does not affect the extent of systemic exposure to mesalamine after single-dose administration of Asacol HD, but mesalamine Cmax decreases by 47 percent and tmax is delayed by 14 hours under fed conditions.

One Asacol HD 800 mg tablet has not been shown to be bioequivalent to two Asacol 400 mg tablets. In a single dose, cross-over pharmacokinetic study in 20 healthy volunteers, the mean mesalamine Cmax was 36 percent lower and the mean mesalamine AUC was 25 percent lower with administration of one Asacol HD 800 mg tablet relative to two Asacol 400 mg tablets. Because the mechanism of action of mesalamine appears to be topical, the impact of these differences in measures of systemic exposure on clinical efficacy is not known.

NONCLINICAL TOXICOLOGY

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 approximately 0.8 and 1.7 times the 4.8 g/day Asacol HD dose (based on body surface area). Mesalamine was not genotoxic in the Ames test, the Chinese hamster ovary cell chromosomal aberration assay, and the mouse micronucleus test. Mesalamine, at oral doses up to 480 mg/kg/day (about 0.8 times the recommended human treatment dose based on body surface area), was found to have no effect on fertility or reproductive performance of male and female rats.

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 4.8 g/day dose for a 50 kg person.)

Mesalamine causes renal papillary necrosis in rats at single doses of approximately 750 mg/kg to 1000 mg/kg (1.3 to 1.7 times the recommended human dose). Doses of 170 and 360 mg/kg/day (about 0.3 and 0.6 times the recommended human dose) 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 (approximately 3.4 times the recommended human dose) for three months produced tubular nephrosis, multifocal/diffuse tubulo-interstitial inflammation, and multifocal/diffuse papillary necrosis.

In dogs, single doses of 6000 mg (approximately 6.25 times the recommended human dose) 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 (0.5 times the recommended human dose).

CLINICAL STUDIES

Moderately Active Ulcerative Colitis

The efficacy of Asacol HD at 4.8 g/day was studied in a six-week, randomized, double-blind, active-controlled study in 772 patients with moderately active ulcerative colitis (UC). Moderately active UC was defined as a Physician’s Global Assessment (PGA) score of 2; the PGA is a four-point scale (0 to 3) that encompasses the clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy findings.

Patients were randomized 1:1 to the Asacol HD 4.8 g/day group (two Asacol HD tablets three times a day) or the Asacol (mesalamine) 2.4 g/day group (two Asacol 400 mg tablets three times a day). (One Asacol HD 800 mg tablet has not been shown to be bioequivalent to two Asacol 400 mg tablets [see Clinical Pharmacology ].)

Patients characteristically had a history of previous use of oral 5-ASAs (86 percent), steroids (41 percent), and rectal therapies (49 percent), and demonstrated clinical symptoms of three or more stools over normal per day (87 percent) and obvious blood in the stool most or all of the time (70 percent). The study population was primarily Caucasian (97 percent), had a mean age of 43 years (8 percent aged 65 years or older), and included slightly more males (56 percent) than females (44 percent).

The primary endpoint was treatment success defined as improvement from baseline to Week 6 based on the PGA. Treatment success rates were similar in the two groups: 70 percent in the Asacol HD group and 66 percent in the Asacol group (difference: 5 percent; 95 percent CI: [-1.9 percent, 11.2 percent]).

A second controlled study supported the efficacy of Asacol HD at 4.8 g/day. Treatment success was 72 percent in patients with moderately active UC treated with Asacol HD.

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