Delayed-Release Oral Mesalamine 4.8 g/day (800-mg Tablet) Is Effective for Patients With Moderately Active Ulcerative Colitis

Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
Gastroenterology (Impact Factor: 16.72). 09/2009; 137(6):1934-43.e1-3. DOI: 10.1053/j.gastro.2009.08.069
Source: PubMed


It is not clear what induction dose of mesalamine is optimal for treating patients with mildly and moderately active ulcerative colitis (UC). This study was conducted to determine the efficacy and safety of mesalamine 4.8 g/day compared with 2.4 g/day for the treatment of moderately active UC.
A multicenter, randomized, double-blind, 6-week, active-control study (ASCEND III) was conducted to assess the noninferiority of delayed-release mesalamine 4.8 g/day (Asacol HD, 800-mg tablet; Procter & Gamble, Pharmaceuticals, Inc, Mason, Ohio) with 2.4 g/day (Asacol, 400-mg tablet; Procter & Gamble Pharmaceuticals, Inc) in 772 patients with moderately active UC. The primary endpoint was treatment success (overall improvement) at week 6, defined as improvement in the Physician's Global Assessment (based on clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy), with no worsening in any individual clinical assessment.
The primary objective of noninferiority was met. Seventy percent (273 of 389) of patients who received 4.8 g/day of mesalamine achieved treatment success at week 6, compared with 66% (251 of 383) of patients receiving 2.4 g/day (95% confidence interval for 2.4 g/day minus 4.8 g/day, -11.2 to 1.9). In addition, 43% of patients who received 4.8 g/day mesalamine achieved clinical remission at week 6 compared with 35% of patients who received 2.4 g/day (P = .04). A therapeutic advantage for the 4.8 g/day dose was observed among patients previously treated with corticosteroids, oral mesalamines, rectal therapies, or multiple UC medications. Both regimens were well-tolerated with similar adverse events.
Delayed-release mesalamine 4.8 g/day (800-mg tablet) is efficacious and well-tolerated in patients with moderately active UC.

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    • "An advantage for doses beyond 2 g was suggested regarding response and mucosal healing but not remission, in the Assessing the Safety and Clinical Efficacy of a New Dose of 5-ASA (ASCEND) II study.66,67 The ASCEND III study suggested a benefit of the higher dose strategy for induction of remission (43% versus 35%; P=0.04),68 while a study with MMX did not demonstrate a benefit of 4.8 g/day compared to 2.4 g/day at 8 weeks.69 "
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    ABSTRACT: In 1977, 5-aminosalicylic acid (5-ASA) was discovered as a therapeutically active moiety of sulfasalazine (SASP) and was launched for topical and oral therapy of ulcerative colitis (UC) in 1984. As a first-step, delivery systems had to be developed to protect 5-ASA against absorption in the upper gastrointestinal tract, resulting in different and competing strategies (azo compounds, controlled release, and pH-dependent release). In a second step, at the beginning of the new century, coinciding with the expiration of patent protection for the first 5-ASA formulations, two component composite release mechanisms (pH-dependent and controlled release) were developed. Furthermore, the drug was formulated as granules instead of tablets, allowing higher unit strengths compared with tablets. Neither Salofalk Granu-Stix®, nor MMX 5-ASA, nor Pentasa® granules have initially been developed for once-daily (OD) dosing. A review of the achievements of 20 years of 5-ASA development has demonstrated that 5-ASA has equal efficacy compared with SASP at best, that there are no measurable differences in efficacy between various 5-ASA preparations, and that in a group of patients tolerating SASP, adverse event profiles of SASP and 5-ASA did not differ significantly, with SASP being the far cheaper substance. Therefore, drug adherence came into focus as a new goal for improving UC therapy. Although adherence is a complex and multifactorial construct, a simple dosing schedule may contribute to higher drug adherence and better efficacy of treatment. Simultaneously, the US 5-ASA market, estimated to be worth US$1.4 billion, is expected to grow continuously. Naturally, this very competitive market is not only driven by scientific progress but also by commercial interests. Thus, patents for minor changes to the formulation may serve as protection against drug companies trying to launch generic versions. Randomized controlled trials performed on OD dosing in induction of remission have demonstrated that OD administration of 5-ASA is as effective as conventional dosing in mild to moderate active UC. The three 5-ASA products MMX, Salofalk®, and Pentasa® employed in those studies so far have not shown differences in efficacy between OD and conventional dosing. No differences regarding safety outcomes have been detected between OD and conventional dosing, including incidence of adverse events, serious adverse events, or withdrawal from treatment due to an adverse event. Although the majority of patients prefer OD dosing to conventional dosing, it was not possible to detect differences in adherence between OD and multiple dose regimens in the clinical trial setting. Well-designed and controlled large-scale community-based studies are necessary to further investigate and prove the point of improved long-term adherence and treatment efficacy in OD dosing.
    Clinical and Experimental Gastroenterology 09/2014; 2014: 7:369 - 383. DOI:10.2147/CEG.S35691
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    • "The ASCEND III study was designed to determine the efficacy and safety of mesalazine 4.8 g/day (Asacol HD, 800-mg tablet) compared with 2.4 g/day (Asacol, 400-mg tablet) in moderately active UC. The results showed that 70% of patients who received 4.8 g/day achieved treatment success at week 6, compared with 66% of patients receiving 2.4 g/day.12 "
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    ABSTRACT: During the last decade a large number of biological agents against tumor necrosis factor-α (TNF-α), as well as many biochemical substances and molecules specifically for the medical treatment of patients with inflammatory bowel disease (IBD), have been developed. This enormous progress was a consequence of the significant advances in biotechnology along with the increased knowledge of the underlying pathophysiological mechanisms involved in the pathogenesis of IBD. However, conventional therapies remain the cornerstone of treatment for most patients. During recent years conventional and biologic IBD therapies have been optimized. Newer mesalazine formulations with a reduced pill size and only one dose per day demonstrate similar efficacy to older formulations. New corticosteroids retain the efficacy of older corticosteroids while exhibiting a higher safety profile. The role of antibiotics and probiotics has been further clarified. Significant progress in understanding thiopurine metabolism has improved the effective dose along with adjunctive therapies. Quite a large number of substances and therapies, including biologic agents other than TNF-α inhibitors, unfractionated or low-molecular-weight heparin, omega-3 polyunsaturated fatty acids, microbes and microbial products, leukocytapheresis, and other substances under investigation, could offer important benefits to our patients. In this paper we review the established and emerging therapeutic strategies in patients with Crohn's disease and ulcerative colitis.
    Drug Design, Development and Therapy 04/2011; 5:185-210. DOI:10.2147/DDDT.S11290 · 3.03 Impact Factor
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    • "The larger ASCEND III trial demonstrated that the magnitude of the therapeutic advantage in patients with moderate UC was somewhat smaller (5%) and not significant [4]. Taken together, the findings from these trials indicated that both 2.4 and 4.8 g/day doses of mesalazine are effective, and thus the lower 2.4 g/day dose might be adequate for patients with mild UC and probably for patients with moderate disease as well [4]. "
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    ABSTRACT: Mesalazine is often used to maintain remission in patients with ulcerative colitis. To investigate if increasing the dose of mesalazine is safe and effective for patients with ulcerative colitis who relapse under low-dose maintenance therapy. Ninety consecutive patients who relapsed during maintenance therapy with oral mesalazine at 1.5-2.25g/day were included. All patients had mildly or moderately active ulcerative colitis at entry, and were treated with oral mesalazine at 4.0g/day for the following 8 weeks. At entry and week 8, endoscopic examinations were carried out to assess the severity of endoscopic inflammation. The primary as well as the secondary endpoints were clinical and endoscopic improvements at week 8. No patient experienced any serious side effect, and the treatment with 4.0g/day mesalazine over the 8 week period was well tolerated by all patients. Fifty-nine patients (66%) achieved clinical improvement in stool frequency and/or rectal bleeding including 40 (44%) with clinical remission (normal stool frequency and no rectal bleeding). Forty-three patients (48%) showed endoscopic improvement including 25 (28%) with endoscopic remission. Increasing the dose of mesalazine up to 4.0g/day appeared to be safe and effective for patients who relapsed under low-dose, 1.5-2.25g/day maintenance therapy.
    Digestive and Liver Disease 12/2010; 43(5):386-90. DOI:10.1016/j.dld.2010.11.016 · 2.96 Impact Factor
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