Source: Health Products Regulatory Authority (IE) Revision Year: 2023 Publisher: Tillotts Pharma GmbH, Warmbacher Strasse 80, DE- 79618 Rheinfelden, Germany
Pharmacotherapeutic group: Intestinal anti-inflammatory agents
ATC code: A07EC02
Asacolon contains mesalazine, also known as 5-aminosalicylic acid, which has an anti-inflammatory effect through a mechanism that has not yet been fully clarified. Mesalazine has been shown to inhibit LTB4-stimulated migration of intestinal macrophages and thus may reduce intestinal inflammation by restricting migration of macrophages to inflamed areas. The production of pro-inflammatory leukotrienes (LTB4 and 5-HETE) in macrophages of the intestinal wall is inhibited. Recently mesalazine has been shown to activate PPAR-γ receptors which counteract nuclear activation of intestinal inflammatory responses.
Under trial conditions mesalazine inhibited the cyclooxygenase and thus, the release of thromboxane B2 and prostaglandin E2, but the clinical meaning of this effect is still unclear. Mesalazine inhibits the formation of platelet activating factor (PAF). Mesalazine is also an antioxidant; it has been shown to decrease formation of reactive oxygen products and to capture free radicals.
One placebo controlled, double-blind trial has been conducted with Asacolon 800 mg GR Tablets including 281 patients with mild to moderate UC. The primary outcome was clinical remission (UCDAI, stool frequency and bleeding scores of 0, and no fecal urgency) at week 6. Due to misclassification of some of the sigmoidoscopy readings at recruitment, a post hoc analysis was performed restricting analysis to UC patients with the endoscopically active disease confirmed by an independent reader.
Overall, 35.1% of patients (40 of 114) in the Asacolon 800 group and 20.9% of patients (23 of 110) in the placebo group showed clinical remission resulting in an absolute difference in remission rate of 14.2% (P = .018; 95% CI of the between-group difference, 2.4%–25.4%).
The efficacy of Asacolon 400 was investigated in a double blind randomized placebo-controlled study including 264 patients. Treatment success Asacolon 400 (0.8 g/day and 1.6 g/day) was comparedby endoscopic evaluation at the 6-month endpoint with the placebo group by using the Fischer exact test. In the intention-to-treat analysis of all patients, 42 of 87 patients (48.3%) in the placebo group had treatment success compared to 57 of the 90 patients (63.3% [CI, 52.8% to 73.8%]) in the group receiving 0.8 g/day (P= 0.050) and 61 of the 87 patients (70.1% [CI, 59.9% to 80.3%]) in the group receiving 1.6 g/day (P= 0.005). Asacolon 400 mg GR Tablets were safe and effective in maintaining remission in quiescent ulcerative colitis.
One open-label study in 15 collaborating centresenrolled 110 CD patients operated for Crohn’s disease by first intestinal resection, of which 47 evaluable patients treated with Asacolon 400 (2.4 g/day) were compared to 48 patients given no treatment. The cumulative proportion of recurrence at 6, 12 and 24 months was significantly lower in the mesalazine group than in the untreated group (P=0.002). At 24 months the cumulative proportions of endoscopic recurrence were 0.52 (±0.12) (±S.E.M.) and 0.85 (±0.07), respectively. The cumulative proportions of severe recurrence was also significantly lower in the Asacolon 400 group 0.17 (±0.09) vs. 0.38 (±0.09); P=0.021. The results of the study indicate that Asacolon 400 mg GR Tablets are safe and delay the recurrence and lessens the severity of the disease at 2 years.
Asacolon tablets are coated with a pH-responsive polymer which enables the release of mesalazine only at a pH above 7, i.e. within the terminal ileum and colon, which are the main sites of inflammation in IBD.
After any initial disruption of the coating mesalazine will continue to be released irrespective of the pH. Asacolon tablets have been designed to minimize the absorption of mesalazine from the digestive tract.
After a single dose of 2.4 g of mesalazine (3 Asacolon 800 mg GR Tablets) in healthy volunteers under fasting conditions quantifiable amounts (>2.00 ng/mL) of mesalazine were observed in plasma after 4.5 h (median tlag).
The geometric mean Cmax-value of mesalazine was 387.86ng/mL with a median tmax of 14.0 h, whereas that of N-acetyl mesalazine was 971.09 ng/mL with an identical median tmax, i.e. 14.0 h.
Based on the recovery of unchanged mesalazine and the main metabolite N-acetyl mesalazine in collected urine after oral fasted administration approximately 23% of the dose (more than 95% as metabolite) was excreted renally within 60 h.
Following concomitant food intake in the same study, a single dose of 2.4 g of mesalazine resulted in quantifiable amounts of mesalazine after 14.5 h (median tlag). The geometric mean Cmax-value of mesalazine was 653.56 ng/mL with a median tmax of about 30.0 h, whereas that of N-acetyl mesalazine was 1245.46 ng/mL with a median tmax of 30.0 h.
Based on the recovery of unchanged mesalazine and the main metabolite N-acetyl mesalazine in collected urine after oral fed administration, approximately 23% of the dose (more than 95 % as metabolite) was excreted renally within 60 h.
Following concomitant food intake the Cmax-values of mesalazine increased 1.69-fold, and the extent of exposure (AUC0-tlast) increased 1.23-fold. Concerning N-acetyl mesalazine after concomitant food intake the Cmax-values increased 1.28-fold, whereas its extent of exposure remained practically unchanged.
About 43% mesalazine and about 78% N-acetyl mesalazine are bound to plasma proteins. Approximately 77 % of the administered dose remains in the gut lumen and the mucosal tissue. The mean apparent volume of distribution per kg of body weight (Vdw) was 147.73 L/kg (geometric mean: 76.06 L/kg) after a single dose of 2.40 g of mesalazine (3 GR tablets of Asacolon 800 mg) in healthy volunteers under fasting conditions. Based upon the absorption of 23.2% of the administered dose, this parameter is equal to 34.27 L/kg (geometric mean: 17.65 L/kg). Low concentrations of mesalazine and N-acetyl mesalazine have been detected in human breast milk. The clinical significance of this has not been determined.
Mesalazine is metabolised both by the intestinal mucosa and the liver to the inactive metabolite N-acetyl mesalazine. About 96% of the drug recovered in the urine after oral administration is found as the main metabolite N-acetyl-mesalazine.
The elimination of mesalazine is essentially urinary and faecal in the form of mesalazine and its N-acetyl metabolite. The geometric mean of total apparent clearance of mesalazine after administration of 2.40 g of mesalazine (3 GR tablets of Asacolon 800 mg) in healthy volunteers under fasting conditions was about 318 L/h (geometric mean, CV% = 137.67%, intersubject). The median elimination half-life was 17 h ranging from 10 to 50 h. About 23% of the total dose administered was recovered in the urine within 60 h after fasted administration mainly as N-acetyl mesalazine and as the parent compound (about 1%).
In a cross-over design with 3 test periods and 3 ascending oral doses of Asacolon 400 mg GR Tablets administered 6 hourly over 4 consecutive doses (total daily dose of mesalazine: 3200, 4800, 6400 mg) it was shown that the absorption and elimination kinetics for mesalazine are dose independent for the 3 doses evaluated. For each dose, about ¾ of the dose was available for the therapeutic activity for the colon. Only about ¼ of each dose was absorbed and excreted in the urine, primarily as the metabolite.
Based on urine drug excretion, plasma drug Cmax's and the combined plasma AUC’s, there was a linear dose response for the 3 Asacolon tablet doses. The clinical performance of Asacolon should be similar for the range of doses evaluated in this study.
No specific studies have been performed.
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
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