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Prolonged-Release Mesalazine

A Review of its Therapeutic Potential in Ulcerative Colitis and Crohn’s Disease

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Summary

Abstract

Prolonged-release mesalazine (Pentasa®2) consists of ethylcellulose-coated microgranules from which mesalazine (known in the US as mesalamine) is released in the small and large intestine in a diffusion-dependent manner.

Dose-dependent improvements in clinical and endoscopic parameters have been reported with prolonged-release mesalazine 2 and 4 g/day in clinical trials in patients with mild to moderately active ulcerative colitis. Induction of clinical and endoscopic remission was achieved in more patients receiving a daily dosage of 4 g/day than in those receiving placebo.

In patients with ulcerative colitis in remission, prolonged-release mesalazine is effective in reducing the rate of relapse. Higher dosages tend to be more effective, and a 12-month remission rate of 64% has been reported for patients treated with a 4g daily dosage of this formulation. Comparative data indicate that prolonged-release mesalazine has similar efficacy in maintaining remission to molar equivalent doses of sulfasalazine.

Data from a study in patients with mild to moderately active Crohn’s disease indicates that higher dosages (4 g/day) of prolonged-release mesalazine are more effective than placebo in reducing disease activity. After 16 weeks’ treatment, 64% of patients receiving a 4 g/day dosage experienced clinical improvement and 43% attained remission. In studies of patients in remission of Crohn’s disease, the formulation appears to be more effective in preventing relapse in patients with isolated small bowel disease than in those with colonie involvement.

The tolerability profile of oral prolonged-release mesalazine is similar to that of placebo and the incidence of adverse events does not appear to be dose-related. Nausea/vomiting, diarrhoea, abdominal pain and dyspepsia occur most frequently, although their incidence is low. Reports of nephrotoxicity during prolonged-release mesalazine treatment are rare.

Conclusions: Oral prolonged-release mesalazine is effective for maintenance and induction of remission of mild to moderately active colitis, both in patients with distal disease and in those with pancolitis. The formulation has similar efficacy to that of equimolar concentrations of sulfasalazine. Prolonged-release mesalazine also appears to be effective in the treatment of Crohn’s disease, and maintenance therapy is of particular value in patients with isolated small bowel involvement. Evidence suggests that higher dosages (3 to 4 g/day) of prolonged-release mesalazine have additional therapeutic benefits over lower dosages in patients with inflammatory bowel disease without increasing the incidence of adverse events.

Mode of Action

The mechanism by which mesalazine exerts its therapeutic actions remains elusive. However, numerous in vitro studies have indicated modulatory actions of mesalazine on the lipid mediators, cytokines and reactive oxygen species involved in the nonspecific inflammation and tissue damage characteristic of ulcerative colitis and Crohn’s disease.

In vitro studies have consistently demonstrated inhibitory effects of mesalazine on leukotriene (LT)B4 synthesis and release from biopsy specimens from individuals with normal colons and from patients with inflammatory bowel disease. Although mesalazine had conflicting effects on prostaglandin (PG)E2 levels, higher concentrations appeared to considerably reduce PGE2 production in colonic mucosa from patients with ulcerative colitis. Mesalazine also appears to reduce in vitro levels of LTC4, 5-hydroxyeicosatetraenoic acid (HETE), 11-, 12-, 15-HETE, PGD2 and platelet-activating factor.

In addition to inhibiting interferon (IFN)-γbinding, mesalazine reduced IFNγ-induced cell permeability and expression of the HLA-DR product of the major histocompatibility complex in colonic epithelial cell lines. Recent evidence suggests that mesalazine reverses the antiproliferative effects of tumour necrosis factor-(TNF)α and inhibits TNFα signalling events in intestinal cells. Mesalazine may also reduce interleukin (IL)-1/1β and IL-2 production.

Mesalazine reduced production of reactive oxygen species and protected against oxidant-induced tissue injury in several in vitro models.

Pharmacokinetic Properties

Entry of water into prolonged-release mesalazine microgranules creates a concentration gradient down which mesalazine diffuses, liberating active drug throughout the small bowel and colon.

Prolonged-release mesalazine acts topically in the affected bowel lumen. In volunteers, 18 to 20% of the administered dose was delivered to the jejunoileal segment as solubilised drug, while cumulative colonic delivery was 82% (approximately 75% as intact microgranules) during the first 7 hours after drug administration. Food intake, local pH and diarrhoeal states do not appear to substantially affect the disposition of mesalazine from the prolonged-release formulation.

Mesalazine is primarily metabolised by acetylation in the gut wall and liver, forming acetyl mesalazine. After oral administration, up to 53% of the administered dose is excreted in the urine as mesalazine plus acetyl mesalazine. Faecal excretion accounts for 40% of the administered dose (14 to 19% as unchanged mesalazine, although exact levels of acetylated and nonacetylated mesalazine in different colonie segments are not known).

Therapeutic Efficacy

Prolonged-release mesalazine at dosages up to 4 g/day has been investigated for the maintenance of remission and treatment of mild to moderately active ulcerative colitis and Crohn’s disease. Higher doses of prolonged-release mesalazine (3 to 4 g/day) were generally more effective than low doses (1.5 to 2 g/day) for treatment of acute exacerbations and for maintenance of disease remission.

At dosages of 2 or 4 g/day, the formulation improved clinical and endoscopic findings in patients with active ulcerative colitis, and success of treatment was independent of disease location. At a dosage of 1.5 g/day, the prolonged-release formulation was as effective as sulfasalazine 3 g/day in improving clinical and endoscopic parameters.

The estimated 1-year remission rate in patients with quiescent ulcerative colitis receiving prolonged-release mesalazine 1.5 g/day was similar to that with sulfasalazine 3 g/day (54 vs 46%). A 4g daily dosage of the mesalazine formulation was more effective than placebo in preventing endoscopie and clinical relapse (1-year remission rates 64 vs 38%).

Low dosages (≤2 g/day) of prolonged-release mesalazine had no significant benefits over placebo in patients with mild to moderately active Crohn’s disease. However, the formulation showed benefits compared with placebo at a dosage of 4 g/day in 1 study. In another study, prolonged-release mesalazine 4 g/day produced improvement, but was not statistically better than placebo. In addition to increasing the percentage of patients in remission, or experiencing therapeutic benefit, prolonged-release mesalazine reduced the time to remission and the percentage of treatment failures, compared with placebo. In another study, 16-week remission rates were significantly higher in patients receiving oral budesonide 9 mg/day than in those treated with a4g daily dosage of prolonged-release mesalazine (62 vs 36%).

During prolonged-release mesalazine treatment for maintenance of remission of Crohn’s disease, dosages of ≤2 g/day were not consistently effective in producing benefits over placebo. However, significantly lower relapse rates were reported in patients treated with a 3g daily dosage than in those receiving placebo over a 48-week period. In a noncomparative study of up to 30 months’ duration, dosages of ≤4 g/day (median 3.7 g/day) were effective in maintaining 72% of patients continuously in remission over a 1-year period. Prolonged-release mesalazine showed particular benefit in reducing the rate of relapse in patients with isolated ileal disease. Endoscopie recurrence rates after 1 year in patients with a recent surgical resection of the affected bowel were significantly lower in those receiving prolonged-release mesalazine 3 g/day than in placebo recipients.

Improvements in disease status have been reported in children (aged 9 to 18 years) receiving prolonged-release mesalazine (22 to 53 mg/kg/day) for the treatment of active Crohn’s disease.

Tolerability

There is no evidence of a dose relationship in the adverse events profile of prolonged-release mesalazine and the tolerability profile is similar to that of placebo. The most common adverse events considered related to treatment with the mesalazine formulation at dosages up to 4 g/day were nausea and/or vomiting, headache, abdominal pain, diarrhoea and dyspepsia. Treatment-related adverse events necessitating study withdrawal occurred less commonly in patients receiving a 4g daily dosage of prolonged-release mesalazine than in those receiving placebo.

Although nephrotoxicity has been associated with the use of other mesalazine-containing preparations, impaired renal function does not appear to be associated with use of the prolonged-release formulation. However, as with other mesalazine preparations, precautionary monitoring of serum creatinine levels has been advocated.

Prolonged-release mesalazine appears to be well tolerated in patients intolerant of sulfasalazine. In patients who had experienced infertility as a result of sulfasalazine treatment, sperm quality was improved or normalised after switching to prolonged-release mesalazine treatment.

Dosage and Administration

Oral prolonged-release mesalazine at dosages up to 4 g/day is indicated for the induction of remission and treatment of mild to moderate ulcerative colitis in adults. For patients with quiescent disease, the recommended starting dosage is 1.5 g/day in 2 or 3 divided doses. However, evidence from clinical trials of dosages up to 4 g/day indicates a dose-dependent increase in efficacy.

No US or UK dosage recommendations are available for the use of prolonged-release mesalazine in the management of Crohn’s disease. However, individualised dosage of up to 4 g/day in divided doses is generally recommended for the treatment of active disease and maintenance of remission in other countries.

Prolonged-release mesalazine should not be used in patients with known sensitivity to salicylates or in those with severe renal and/or liver impairment, and is not recommended for use in children. The formulation should be used with caution during pregnancy.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 10, New Zealand

    Delyth Clemett & Anthony Markham

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  1. Delyth Clemett
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Correspondence to Delyth Clemett.

Additional information

Also known as mesalamine in the US

Various sections of the manuscript reviewed by: V.A. Botoman, Department of Gastroenterology, Cleveland Clinic, Fort Lauderdale, Florida, USA; P.D. Layer, Department of Internal Medicine, Israelitic Hospital, Hamburg, Germany; Y.R. Mahida, Division of Gastroenterology, University Hospital, Nottingham, UK; N.A. Punchard, Department of Biology and Health Science, University of Luton, Luton, UK; S.N. Rasmussen, Department of Medical Gastroenterology, Hvidovre University Hospital, Copenhagen, Denmark; M. Robinson, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma, USA; B.N. Singh, Department of Industrial Pharmacy, St John’s University, New York, New York, USA; J.W. Singleton, Division of Gastroenterology & Hepatology, University of Colorado Health Sciences Center, Denver, Colorado, USA.

Data Selection

Sources: Medical literature published in any language since 1983 on Mesalazine, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand) and Medline. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: AdisBase search terms were ‘Mesalazine’ or ‘Mesalamine’ or ‘5-ASA’ and (‘Inflammatory-bowel-disorders’ or ‘Proctitis’) and (‘slow-release’ or ‘prolonged-release’). Medline search terms were ‘Mesalazine’ or ‘Mesalamine’ or ‘5-ASA’ and (‘Inflammatory-boweldiseases’ or ‘Crohn-disease’ or ‘Ulcerative-colitis’ or ‘Proctitis’) and ‘slow-release’. Searches were last updated 20 Mar 2000.

Selection: Studies in patients with ulcerative colitis or Crohn’s disease who received oral prolonged-releasemesalazine (Pentasa®). Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Mesalazine, mesalamine, Pentasa®, ulcerative colitis, Crohn’s disease, pharmacodynamics, pharmacokinetics, therapeutic

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Clemett, D., Markham, A. Prolonged-Release Mesalazine. Drugs 59, 929–956 (2000). https://doi.org/10.2165/00003495-200059040-00016

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