Asacol 400
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Asacol 400 - Scientific Information

Manufacture: Warner Chilcott
Country: Canada
Condition: Ulcerative Colitis
Class: Gastrointestinal agents
Form: Tablets
Ingredients: 5-aminosalicylic aciddibutyl phthalate, edible black ink (ammonium hydroxide, n-butyl alcohol, shellac glaze [modified] in SD-45, synthetic black iron oxide and propylene glycol), iron oxide red, iron oxide yellow, lactose, magnesium stearate, Eudragit-S {methacrylic acid copolymer Type B (USP)}, polyethylene glycol, polyvinylpyrrolidone, sodium starch glycolate, colloidal silicon dioxide and talc

Pharmaceutical Information

Drug Substance

INN: mesalazine
USAN: mesalamine
Chemical Name: 5-amino-2-hydroxybenzoic acid, also referred to as 5-aminosalicylic acid or
5-ASA.
Structural Formula:


Molecular Formula: C7H7NO3
Molecular Weight: 153.1
Description: Mesalamine is an off-white to light-brown powder that decomposes at 280°C and is slightly soluble in water. It darkens upon exposure to air, high humidity or light over a period of several months.
pKa Values: pK1 = 2.74, pK2 = 5.80.

Clinical Trials

Mildly to moderately active ulcerative colitis

In a randomized, double-blind, placebo-controlled clinical trial it was shown (see chart below) that Asacol (4.8 g/day of mesalamine in divided doses) was highly effective in inducing remission in ulcerative colitis patients with active disease.

Overall Outcome of Physicians Global Assessment



Maintenance of remission of ulcerative colitis

A 6 month, randomized, double-blind, placebo-controlled, multi-centre study involved 264 patients treated with Asacol 0.8 g/day (n=90), 1.6 g/day (n=87), or placebo (n=87). The proportion of patients treated with 0.8 g/day who maintained endoscopic remission was not statistically significant compared to placebo. In the ITT analysis of patients treated with Asacol 1.6 g/day, Asacol maintained endoscopic remission of ulcerative colitis in 61 of 87 (70.1%) of patients, compared to 42 of 87 (48.3%) of placebo recipients (p=0.005).

A pooled efficacy analysis of 4 maintenance trials compared Asacol (0.8 to 2.8 g/day) with sulfasalazine (2 to 4 g/day). Treatment success was 58 of 98 (59%) for Asacol and 70 of 102 (69%) for sulfasalazine, a non-significant difference.

Additional double-blind clinical trials of 16, 24, and 52 weeks duration have shown Asacol in doses ranging from 0.8 to 4.4 g/day to be as effective as sulfasalazine for maintenance of remission. It is particularly noteworthy that most patients intolerant or allergic to sulfasalazine can be effectively maintained in remission on Asacol as demonstrated in open-labeled clinical trials. In addition, male infertility resulting from sulfasalazine therapy has been shown to be reversible upon treatment with Asacol.

Detailed Pharmacology

Pharmacokinetics

Mesalamine release from Asacol is delayed until the terminal ileum as reflected by tmax’s of about 7 hours for mesalamine and its metabolite, N-acetyl-5-aminosalicylic acid. The t1/2elm’s were about 3 hours for mesalamine and 10 hours for N-acetyl-5- aminosalicylic acid.

Human studies conducted using radiological and serum markers showed that the Asacol coating delayed release of mesalamine until the terminal ileum was reached. Other studies compared mesalamine absorption when administered as an enema (a readily available dosage form) and when released for absorption in the stomach, small intestine, and colon relative to an intravenous dose. Once released in the colon, mesalamine was minimally absorbed and plasma levels were similar to those found following rectal administration. Approximately 20% of the administered dose released was absorbed, with about 80% available for topical activity in the colon. The absorbed mesalamine was rapidly acetylated through the gut mucosal wall and by the liver. It was mainly excreted by the kidney as N-acetyl-5-aminosalicylic acid.

Serum levels and urinary excretion of mesalamine and N-acetyl-5-aminosalicylic acid following single and multiple equimolar Asacol and sulfasalazine doses to healthy subjects and to patients were compared. There was no consistent trend for greater serum mesalamine or metabolite levels following Asacol dosage. Based on urinary dose recoveries, the extent of mesalamine absorption for Asacol was no greater than that for sulfasalazine. Overall, there were no meaningful differences in the extents of mesalamine absorption following equimolar Asacol and sulfasalazine doses.

In another study, there was a dose response in serum mesalamine and metabolite levels at Asacol doses of 1.2 and 2.4 g/day. In other studies when Asacol was administered at higher or lower doses than 1.2 and 2.4 g/day, serum mesalamine and N-acetyl-5-aminosalicylic acid concentrations differed from those for the 1.2 and 2.4 g/day doses as would be expected following a linear dose response relationship. The effects of co-administration of Asacol with cimetidine, an antacid containing activated simethicone and aluminum hydroxide, and antacid with a high fat meal were addressed in another study. There were no significant in vivo effects on mesalamine release or the extent of drug absorption from Asacol by any of the three treatments.

Toxicology

Acute Toxicity Studies

The acute peroral LD50 value for mesalamine is reported to be 5000 mg/kg in mice and 4594 mg/kg in rats.

Subacute Toxicity Studies

Rats (2/sex/group) were administered mesalamine orally at dosages of 0, 40, 120, 360, and 1080 mg/kg/day for 14 days. One female rat (1080 mg/kg/day) died, most probably of renal failure complicated by gastric mucosal injury. Drug-related changes in the clinical chemistry assays (increased serum urea nitrogen, serum creatinine and serum total proteins, and decreased albumin/globulin ratios) occurred only at the 1080 mg/kg/day level. Drug-related histomorphologic effects were present in the kidneys (1080 mg/kg/day) and gastrointestinal tracts (360 and 1080 mg/kg/day) of treated rats.

A similar study in rabbits resulted in diarrhea during the first week (males, 1080 mg/kg/day). Urinalysis revealed slight increases in proteinuria, bilirubinuria, and urinary acetone in the high dose group.

No drug-related effects were observed when rabbits were given 227.3 mg/kg/day rectally (suppository) for 12 days.

Chronic Toxicity Study

Dogs (2/sex/group) were administered Asacol tablets at oral dosages of 40, 120, and 200 mg/kg/day for one year. Control dogs received placebo tablets. Histopathology and clinical chemistry assessment showed no evidence of drug-related effects.

Teratology Studies

No evidence of teratogenicity was observed when mesalamine was administered orally at a dosage of 480 mg/kg/day to pregnant rats and rabbits.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Dietary mesalamine was determined not to be carcinogenic in rats at doses as high as 480 mg/kg/day in one two year study, and 840 mg/kg/day in a second two year study. Similarly, dietary mesalamine was not carcinogenic in mice at 2000 mg/kg/day. These doses are 15, 26 and 62.5 times the maximum recommended human maintenance dose of Asacol of 1.6 g/day (32 mg/kg/day if 50 kg body weight assumed.)

Mesalamine was not mutagenic in two bacterial test systems (Ames assay and K. pneumoniae test) with and without metabolic activation.

The effects of oral mesalamine on fertility and gestation indices were investigated in rats at doses up to 480 mg/kg/day. No effects on fertility or gestation parameters were noted in these studies.

Special Studies: Two studies to assess the potential renal toxicity of mesalamine in a rat model have been reported in the literature. In an acute study, rats were given a single massive intravenous injection, at dose levels between 214 and 872 mg/kg. The animals killed 24-96 hours after the injection presented lesions in the proximal cortical tubules as well as renal papillary necrosis. The former lesion was reversible by one week post-administration. In a second study, using a more clinically relevant dosing regimen, rats were dosed up to 200 mg/kg p.o. for 4 weeks. No drug-related effects were observed.