Asacol 800
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Asacol 800 - Scientific Information

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

Pharmaceutical Information

Drug Substance

Proper name: mesalamine or 5- aminosalicylic acid
Chemical Name: 5-amino-2-hydroxybenzoic acid, also referred to as 5-aminosalicylic acid or 5-ASA.
Molecular formula and molecular mass: C7H7NO3 Molecular Weight 153.1
Structural formula:


Physicochemical properties: Physicochemical properties: 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

Study demographics and trial design

In the pivotal double-blind, randomized, multiple-site, controlled study in newly and previously diagnosed patients who were experiencing a flare-up of mildly to moderately active ulcerative colitis, patients were randomly assigned to receive either 2.4 g/day (Asacol 400 mg tablet) or 4.8 g/day (Asacol 800 (800 mg tablet)) for 6 weeks. A total of 301 patients were randomized to the treatment groups. In this study, a large subgroup (n = 180) of patients with moderately active ulcerative colitis was identified using the predefined stratum of baseline disease severity. Additional analyses looking at the primary, secondary and tertiary efficacy endpoints were performed in this subgroup of patients. The data from these analyses supports the efficacy of Asacol 800 (800 mg tablet) at 4.8 g/day in moderately active ulcerative colitis patients.

In the pivotal clinical trial with Asacol 800 (800 mg tablet), moderately active ulcerative colitis was determined by a Physician Global Assessment (PGA) which included clinical and endoscopic evaluations scored as a 2 on a 0 (normal) to 3 (severe) scale.

The baseline demographic characteristics for the moderately active ulcerative colitis patients are presented in Table 1.

Table 1 Summary of baseline demographic characteristics for patients with moderately active ulcerative colitis
Dosage, route of
administration and
duration
Study subjects
(n=number)
Mean age
(Range)
Gender
2.4 g/day (400 mg
tablets orally for 6
weeks)
n=96 43.0

(18-74)
45.8% M

54.2% F
4.8 g/day (800 mg
tablets orally for 6
weeks)
n=84 45.4

(20-76)
47.6% M

52.4% F

There were no statistically significant differences for any baseline demographic or anthropometric characteristic, or history of ulcerative colitis between patients with moderately active ulcerative colitis enrolled into the two treatment groups. With respect to baseline disease state characteristics, patients in the two treatment groups were not statistically different except for stool frequency scores in which more patients in the 4.8 g/day group had slightly higher stool frequency scores.

Patients enrolled into the study presented with either proctitis, proctosigmoiditis, left-sided colitis, or pancolitis and the length of disease ranged from less than one year to greater than 10 years.

In another double-blind, randomized, multiple-site, controlled study (Study 2) in newly and previously diagnosed patients who were experiencing a flare up of moderately active ulcerative colitis, patients were randomly assigned to receive either 2.4 g/day (Asacol 400 mg tablet) or 4.8 g/day (Asacol 800 (800 mg tablet)) for 6 weeks. A total of 386 patients were randomly assigned to treatment groups; 268 with moderate disease. The two moderately active ulcerative colitis treatment groups were comparable with respect to baseline demographic, disease history, and disease severity characteristics. Results from this study support the efficacy of Asacol 800 (800 mg tablet) at 4.8 g/day in moderately active ulcerative colitis patients.

Study Results

In both studies, the percentage of patients with moderately active ulcerative colitis who were classified as a treatment success after 6 weeks of therapy based on the intent-to-treat study population are presented in Table 2.

Table 2 Summary of Treatment Outcomes at Week 6 (Intent-to-treat Population With Moderate Disease [PGA = 2] at Baseline)
Treatment Outcome 2.4 g/day Asacol
(400 mg Tablet)
(N = 223)
n
(%)
4.8 g/day Asacol
(800 mg Tablet)
(N = 200)
n (%)
p-value (b)
Pivotal Study
Treatment Success (a) 53 (57.0%) 55 (72.4%) 0.0384
Treatment Failure 40 (43.0%) 21 (27.6%)
Study 2
Treatment Success (a) 77 (59.2%) 89 (71.8%) 0.0357
Treatment Failure 53 (40.8%) 35 (28.2%)
Pooled
Treatment Success (a) 130 (58.3%) 144 (72.0%) 0.0034
Treatment Failure 93 (41.7%) 56 (28.0%)
N = number of patients in treatment group (pooled) with treatment outcome at Week 6
n (%) = number and percentage (n/Total x 100) of patients in treatment with specified outcome
(a) Treatment success was defined as improvement from baseline at Week 6. Improvement from baseline was defined as either a complete response (remission) or partial response (improvement) to treatment. A complete response was defined as a PGA score of 0 and complete resolution of the following clinical assessments: stool frequency, rectal bleeding, PFA, and sigmoidoscopy findings. A partial response was defined as improvement from baseline in the PGA score, accompanied by improvement from baseline in at least 1 of the clinical assessments listed above, and no worsening in any of the remaining clinical assessments. Treatment failure was defined as: 1) PGA score that stayed the same or worsened from baseline (regardless of whether the other clinical assessments resolved), 2) worsening of any clinical assessments at Week 6, or 3) withdrawal from the study due to an AE or lack of treatment effect.
(b) 4.8 g/day compared to 2.4 g/day, from Chi-square test for 2000082 and 2000083, and stratified by protocol using the Cochran-Mantel-Haenszel test for pooled analysis.

The results of these studies for moderately active disease patients are consistent with those of a previous trial, in which the majority of patients were moderate disease patients (77%), where 4.8 g/day was administered using Asacol 400 mg tablets and 74% of patients were classified as treatment success. The findings in the Asacol 800 (800 mg tablet) studies are consistent with the fact that a higher dose of mesalamine shows greater efficacy in patients with more severe disease. Demonstrated efficacy of the Asacol 800 (800 mg tablet) tablet, administered at 4.8 g/day in the population of patients with moderately active disease, provides this population with an alternate formulation allowing daily ingestion of fewer tablets.

Physician’s Global Assessment and Individual Symptom and Sigmoidoscopy Scores at Weeks 3 and 6

The percentage of patients whose individual clinical assessments (stool frequency score, rectal bleeding score, and PFA score), sigmoidoscopy score, and PGA score improved from baseline at Weeks 3 and 6 from both studies (pooled data) are presented in Table 3.

Table 3 Distribution of Treatment Improvement for Physician's Global Assessment and Individual Symptoms at Weeks 3 and 6 Excluding Patients With Both Baseline and Visit Scores of Zero (Patients with Moderate Disease [PGA = 2] at Baseline)
Parameter Visit 2.4 g/day Asacol
(400 mg Tablet)
(N = 223)
n (%)
4.8 g/day Asacol
(800 mg Tablet)
(N = 200)
n (%)
PGA Week 3 122 (63.5%) 130 (71.8%)
Week 6 139 (73.2%) 152 (84.9%)*
Stool Frequency Week 3 107 (59.4%) 112 (64.7%)
Week 6 126 (70.8%) 126 (75.4%)
Rectal Bleeding Week 3 110 (65.5%) 128 (74.4%)
Week 6 130 (76.5%) 137 (81.5%)
PFA Week 3 100 (62.5%) 90 (58.8%)
Week 6 114 (70.8%) 108 (72.0%)
Sigmoidoscopy Week 3 110 (57.3%) 111 (61.3%)
Week 6 129 (67.9%) 140 (78.2%)*
Patients with no treatment outcome at Week 6 were excluded from this analysis. For patients who have a baseline score but have no score at visit, the improvement status cannot be determined. These patients were also excluded from this analysis.
* = Between-treatment difference is statistically significant (p<0.05) using the Cochran-Mantel-Haenszel test stratified by protocol.
N = number of patients in treatment group with treatment outcome at Week 6
n(%) = number and percentage (n/Total x 100) of patients in treatment with specified outcome in specified parameter

In both studies, more patients showed improvement on 4.8 g/day compared to 2.4 g/day across the clinical assessments (stool frequency, rectal bleeding, sigmoidoscopy and PGA). From pooled results, 4.8 g/day showed statistically significant superiority in the sigmoidoscopy and PGA scores at 6 weeks.

Results from both studies (pooled data) demonstrate that the median time to resolution of increased stool frequency, rectal bleeding, and the composite of both symptoms were shorter for the 4.8 g/day group than for the 2.4 g/day group. In addition, the difference between groups was statistically significant for the median time to resolution of rectal bleeding (9 days for 4.8 g/day group vs 16 days for 2.4 g/day group) and the composite of both symptoms (19 days for 4.8 g/day group vs 29 days for 2.4 g/day group), favouring the 4.8 g/day group.

Quality-of-life Scores

The quality-of-life scores derived from the Inflammatory Bowel Disease Questionnaire (IBDQ) at Weeks 3 and 6 from both studies (pooled data) are presented in Table 4.

Table 4 Mean Change from baseline in Inflammatory Bowel Disease Questionnaire Scores at Weeks 3 and 6 (Patients with Moderate Disease [PGA = 2] at Baseline)
Category 2.4 g/day Asacol
(400 mg Tablet)
(N = 235)
4.8 g/day Asacol
(800 mg Tablet)
(N = 213)
n Mean n Mean
Total
Week 3 189 30.1* 183 33.7*
Week 6 183 42.6* 176 45.0*
Exit 212 36.4* 193 40.2*
Bowel
Week 3 190 11.4* 182 13.1*
Week 6 183 16.4* 176 17.4*
Exit 212 14.4* 193 15.6*
Systemic
Week 3 191 4.3* 184 5.1*
Week 6 185 6.1* 177 6.8*
Exit 214 5.2* 194 5.9*
Emotional
Week 3 187 9.9* 181 11.1*
Week 6 182 13.9* 175 14.8*
Exit 211 11.8* 192 13.2*
Social
Week 3 191 4.2* 182 4.6*
Week 6 186 5.9* 176 5.9*
Exit 215 4.7* 193 5.3*
Exit is the Week 6 visit for those who completed the study and the withdrawal visit for those who dropped out.
N = number of patients in treatment group with treatment outcome at Week 6
n = number of patients from which statistics were calculated.
* = Change from baseline using t-test is statistically significant (p<0.0001).

Quality of life pooled data from both studies using the IBDQ showed statistically significant improvement from baseline in both treatment groups at both week 3 and week 6. No statistically significant differences were seen between treatment groups; however, there was a trend for scores to favour 4.8 g/day dosing over 2.4 g/day dosing.

Detailed Pharmacology

Mesalamine release from Asacol 800 (800 mg tablet) is delayed until the terminal ileum as reflected by the time to peak plasma concentration (tmax) that is approximately 10 hours or greater for mesalamine and its metabolite, N-acetyl-5-ASA. The terminal elimination half-life (t1/2elm) is 12 to 19 hours for both mesalamine and N-acetyl-5-ASA.

Human studies conducted using radiological and serum markers, with the 400 mg tablets, showed that the Asacol (400 mg tablet) coating delayed release of mesalamine until the terminal ileum was reached. Other studies with mesalamine compared its 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. Results indicated that 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-ASA.

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 (400 mg tablet) 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.