, Volume 57, Issue 3, pp 383-408
Date: 10 Oct 2012

Oral Delayed-Release Mesalazine

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Summary

Abstract

Oral delayed-release mesalazine is an enteric-coated formulation which releases mesalazine in the terminal ileum and colon.

Up to 74% of patients with mild to moderately active ulcerative colitis experience endoscopic or symptomatic improvement (including remission) or both when treated with oral delayed-release mesalazine 2.4 to 4.8 g/day. There is a trend towards a better response in patients receiving higher daily dosages of oral delayed-release mesalazine, especially in patients with active distal disease. In patients with left-sided ulcerative colitis, oral balsalazide 6.75 g/day appears to be more effective than oral delayed-release mesalazine 2.4 g/day, but a higher dosage of oral delayed-release mesalazine 4.8 g/day may provide additional benefit in these patients.

Oral delayed-release mesalazine 0.8 to 4.4 g/day appears to be as effective as sulfasalazine 2 to 4 g/day, prolonged-release mesalazine 1.5 g/day or balsalazide 3 g/day in maintaining remission in patients with ulcerative colitis. The optimal dosage of oral delayed-release mesalazine for the maintenance of remission is unclear. However, oral delayed-release mesalazine 1.6 g/day with rectal mesalazine 4g, administered twice weekly, was more effective than oral drug alone in maintaining remission in patients at high risk of relapse. In patients with left-sided or distal disease oral olsalazine 1 g/day appeared to be superior to oral delayedrelease mesalazine 1.2 g/day for maintenance of symptomatic remission.

Limited data in patients with Crohn’s disease have shown oral delayed-release mesalazine 0.4 to 4.8 g/day to be an effective therapy for active disease (remission in up to 45% of patients) and for quiescent disease (relapse in 34% of recipients over a duration of up to 12 months). Preliminary data indicate that oral delayedrelease mesalazine 2.4 g/day is effective in preventing postoperative recurrence of Crohn’s disease. Oral delayed-release mesalazine is effective and well tolerated in sulfasalazine-intolerant patients with ulcerative colitis or Crohn’s disease.

Conclusions: Oral delayed-release mesalazine is effective in patients with mild to moderately active or quiescent ulcerative colitis. Available data suggest that patients with left-sided or distal ulcerative colitis are likely to require higher daily dosages of oral delayed-release mesalazine or supplementation with rectal mesalazine. Oral delayed-release mesalazine also appears to be effective in active and quiescent Crohn’s disease. The drug is well tolerated and it appears to be effective in sulfasalazine-intolerant patients.

Mechanism of Action

Delayed-release mesalazine is coated with an 80 to 130μm layer of Eudragit® S, which dissolves at pH ≥7 and releases the active drug in the terminal ileum and colon.

Although the exact mechanism of action of mesalazine in patients with ulcerative colitis and Crohn’s disease is not known, in vitro studies have indicated various possible ways in which the drug may provide benefit in these patients. These include inhibition of eicosanoids, inhibition of cytokines and modulation of their effects and protection against oxygen-derived free radicals.

Most studies have shown that mesalazine concentration-dependently inhibits in vitro leukotriene (LT)B4 production in colonic mucosal cells from biopsy specimens from patients with inflammatory bowel disease and from patients with healthy colons, and in peripheral mononuclear leucocytes from healthy volunteers. Mesalazine did not affect in vitro prostaglandin (PG)E2 production in biopsy specimens from healthy volunteers but tended to normalise the increased PGE2 levels in biopsy specimens from patients with active ulcerative colitis. Other in vitro studies indicate that mesalazine may also decrease levels of LTC4, PGD2, 5-hydroxyeicosatetraenoic acid (HETE) and 11-, 12- and 15-HETE.

Mesalazine showed concentration-dependent inhibition of oxygen-derived free radical generation and concentration-dependent protection against oxidant-induced injury in various in vitro models.

Interferon (IFN)-γ binding and IFNγ-induced effects, such as expression of major histocompatibility gene complex D-related (HLA-DR) and increased cellular permeability, are also inhibited by mesalazine in cultures of standard colonic epithelial cell lines. Mesalazine may also decrease interleukin (IL)-1/1β and IL-2 production and reduce IL-2 receptor expression.

Pharmacokinetic Properties

Orally administered delayed-release mesalazine acts locally from within the lumen of the inflamed bowel and is partly absorbed into the systemic circulation. Mean steady-state mesalazine concentrations of 298.5 ng/mg wet tissue weight were found in ileocolonic biopsy specimen homogenates from patients with irritable bowel syndrome after 7 days’ treatment with oral delayed-release mesalazine 1.2 g/day. After 7 days’ treatment with other mesalazine formulations or prodrugs, containing nearly equal amounts of mesalazine, the tissue concentrations were 3-to 1000-fold lower than with oral delayed-release mesalazine. Rectal mucosal mesalazine concentrations increased dose-dependently after oral delayed-release mesalazine.

Mesalazine is primarily acetylated, to its major metabolite N-acetyl-5-aminosalicylic acid (Ac-5-ASA), in the gut wall and the liver. After oral administration of delayed-release mesalazine, up to 44% of the administered dose is excreted in the faeces as mesalazine or Ac-5-ASA. Renal excretion of mesalazine and Ac-5-ASA accounts for up to 35.6% of the administered dose. The release of mesalazine after administration of oral delayed-release mesalazine does not appear to be affected by diarrhoea or by concurrent administration of omeprazole, famotidine or a high fibre diet with ispaghula husk.

Therapeutic Efficacy

Oral delayed-release mesalazine ≥2.4 g/day is generally effective in patients with mild to moderately active ulcerative colitis. Preliminary data indicate that oral delayed-release mesalazine 0.4 to 4.8 g/day is also effective in patients with active Crohn’s disease. Dosages ≤2.4 g/day are commonly used to maintain remission in patients with ulcerative colitis or Crohn’s disease. Oral delayed-release mesalazine appears to be effective in patients with sulfasalazine intolerance.

Oral delayed-release mesalazine 2.4 to 4.8 g/day led to endoscopie and/or symptomatic improvement (including remission) in up to 74% of patients with mild to moderately active ulcerative colitis. In 3 trials, patients receiving higher daily dosages of oral delayed-release mesalazine tended to experience greater improvement than those receiving lower daily dosages, especially in patients with active distal disease. Oral balsalazide 6.75 g/day was more effective than oral delayed-release mesalazine 2.4 g/day in inducing remission in patients with active, moderate to severe left-sided ulcerative colitis in one trial. Patients with left-sided disease were reported to be more resistant to treatment than those with extensive disease. However, endoscopic and symptomatic improvement in patients with left-sided disease was greater with oral delayed-release mesalazine 4.8 g/day than with 1.6 g/day, suggesting that higher dosages may offer additional benefit in these patients. Significantly greater numbers of patients with active distal disease receiving oral delayed-release mesalazine 2.4 g/day with mesalazine 4g rectal suspension enema once nightly showed symptomatic improvement than those receiving oral drug alone. Endoscopic and symptomatic improvement in patients with active distal disease receiving oral delayed-release mesalazine 3.2 g/day was similar to that in patients receiving prednisolone metabenzoate enema 20mg twice daily.

Relapse rates in patients with ulcerative colitis receiving oral delayed-release mesalazine 0.8 to 4.4 g/day (22 to 38% of patients) were similar to those with oral sulfasalazine 2 to 4 g/day, oral prolonged-release mesalazine 1.5 g/day or oral balsalazide 3 g/day in randomised, single- or double-blind trials of up to 12 months’ duration. The optimum dosage of oral delayed-release mesalazine for maintaining remission in patients with quiescent extensive ulcerative colitis remains unclear. Patients with left-sided or distal disease and those with short duration of remission may benefit from higher dosages of mesalazine. Oral administration of olsalazine 1 g/day (n = 42) appeared to be more effective than oral delayedrelease mesalazine 1.2 g/day (n = 40) in maintaining symptomatic remission in patients with left-sided ulcerative colitis (relapse in 12 vs 33% of patients). Oral delayed-release mesalazine 1.6 g/day with rectal mesalazine enema, 4g administered twice weekly, was significantly more effective than oral drug alone in preventing relapse over a period of 12 months in patients with ulcerative colitis at high risk of relapse (history of ≥2 relapses in the last 12 months).

There are limited data on the use of oral delayed-release mesalazine in patients with active or quiescent Crohn’s disease. Oral delayed-release mesalazine 3.2 g/day led to remission in 45% of recipients (n = 20) compared with similar improvement in 22% of placebo recipients (n = 18) in a trial in patients with mild to moderately active Crohn’s disease. 34% of patients with quiescent Crohn’s disease receiving oral delayed-release mesalazine 2.4 g/day relapsed during a 12-month trial period (versus 55% receiving placebo). Oral delayed-release mesalazine may be particularly effective in preventing symptomatic relapse in patients with Crohn’s disease restricted to the ileum and in those with mild disease. Endoscopic recurrence rates after 24 months, in patients with Crohn’s disease who underwent a first radical resection of the inflamed bowel, were significantly lower in oral delayed-release mesalazine 2.4 g/day recipients than in those who received no treatment (52 vs 85% of patients).

Tolerability

Oral delayed-release mesalazine appears to be well tolerated in patients who are intolerant to sulfasalazine. The incidence of gastrointestinal adverse events such as nausea, diarrhoea and dyspepsia, was greater with oral delayed-release mesalazine 1.6 or 2.4 g/day than with placebo in patients with mild to moderately active ulcerative colitis. The most common adverse events in patients treated with oral delayed-release mesalazine 2.4 g/day included headache, gas, nausea, diarrhoea and dyspepsia. Adverse events with oral delayed-release mesalazine 0.024 to 7.2 g/day necessitated drug withdrawal in up to 11% of patients in 3 large (n = 4717), prospective long term noncomparative trials. No serious adverse events were reported in these trials. The results of one retrospective trial indicate that oral delayed-release mesalazine 15 to 88 mg/kg is well tolerated in children, aged 4 to 19 years, with inflammatory bowel disease.

It has been estimated that serious renal impairment with oral delayed-release mesalazine will occur in fewer than 1 per 500 recipients. Early detection of renal impairment and prompt drug withdrawal (after ≤10 months of mesalazine administration) has been reported to lead to complete recovery of renal function in 5 of 6 patients. Available data suggest that all mesalazine-delivering drugs share the potential to cause nephrotoxicity, and monitoring of renal function of patients receiving these agents is recommended.

Ddosage and Administration

Oral delayed-release mesalazine 2.4 g/day, with concomitant corticosteroids where necessary, is recommended for the treatment of mild to moderately active ulcerative colitis in adults. However, oral delayed-release mesalazine has been used in daily doses of up to 4.8g in trials in patients with active, mild to moderate ulcerative colitis. For adult patients with quiescent ulcerative colitis, oral delayed-release mesalazine 1.2 to 2.4 g/day is recommended for maintenance of remission. However, depending on the duration of remission and the site of disease mesalazine may be used in dosages of up to 4 g/day in patients with quiescent ulcerative colitis.

No recommendations are available regarding the dosage of oral delayed-release mesalazine in patients with active Crohn’s disease. In patients with active Crohn’s disease, oral delayed-release mesalazine 3.2 g/day was more effective than placebo in inducing remission in one trial, but oral dosages ranging from 0.4 to 4.8 g/day have been used in other trials. Oral delayed-release mesalazine 1.2 to 2.4 g/day is recommended for the maintenance of remission in patients with Crohn’s ileo-colitis. The drug may be particularly effective in prolonging remission in patients with quiescent Crohn’s disease in whom the disease is restricted to the ileum or in those with mild disease.

Oral delayed-release mesalazine should not be used in patients with renal sensitivity to sulfasalazine or a history of hypersensitivity to salicylates, in patients with severe renal impairment or in children less than 2 years of age.

Various sections of the manuscript reviewed by: G. d’Albasio, Divisione di Gastroenterologia, Azienda Ospedaliera Careggi, Careggi, Florence, Italy; A. Forbes, St. Mark’s Academic Institute, St. Mark’s Hospital, Harrow, Middlesex, England; P. Gionchetti, Dipartimento di Medicina Interna e Gastroenterologia, Università di Bologna, Bologna, Italy; D.P. Jewell, Gastroenterology Unit, Department of Medicine, Radcliffe Infirmary, Oxford, England; J.M. Rhodes, Gastroenterology Research Group, University Clinical Department of Medicine, The University of Liverpool, Liverpool, England; G.N.J. Tytgat, Department of Gastroenterology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; M.J. World, Department of Military Medicine, Royal Defence Medical College, Gosport, England.

Data Selection

Sources: Medical literature published in any language since 1966 on delayed-release mesalazine, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand), Medline and EMBASE. 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’ and ‘inflammatory bowel disorders’. Medline and EMBASE search terms were ‘mesalazine’, ‘mesalamine’, ‘inflammatory bowel diseases’ and ‘inflammatory bowel disorders’. Searches were last updated 12 Jan 1999.
Selection: Studies in patients with ulcerative colitis or Crohn’s disease who received oral delayed-release mesalazine. 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: Oral delayed-release mesalazine, ulcerative colitis, Crohn’s disease, pharmacokinetics, pharmacodynamics, therapeutic use, tolerability, dosage and administration.