Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Ferring Ireland Ltd, United Drug House, Magna Drive, Magna Business Park, Citywest Road, Dublin 24, Ireland
Pharmacotherapeutic group: Intestinal anti-inflammatory agents
ATC Code: A07EC02
It has been established that mesalazine is the active component of sulphasalazine which is used for the treatment of ulcerative colitis and Crohn’s disease. Based on clinical results, the therapeutic value of mesalazine after oral as well as rectal administration appears to be due to local effect on the inflamed intestinal tissue, rather than to systemic effect. There is information suggesting that severity of colonic inflammation in ulcerative colitis patients treated with mesalazine is inversely correlated with mucosal concentrations of mesalazine.
Increased leucocyte migration, abnormal cytokine production, increased production of arachidonic acid metabolites, particularly leukotriene B4 and increased free radical formation in the inflamed intestinal tissue are all present in patients with inflammatory bowel disease.
The mechanism of action of mesalazine is not fully understood although mechanisms such as activation of the γ-form of peroxisome proliferator-activated receptors (PPAR-γ) and inhibition of nuclear factor-kappa B (NF-κB) in the intestinal mucosa has been implicated.
Mesalazine has in-vitro and in-vivo pharmacological effects that inhibit leucocyte chemotaxis, decrease cytokine and leukotriene production and scavenge for free radicals.
It is currently unknown which, if any of these mechanisms play a predominant role in the clinical efficacy of mesalazine.
The therapeutic activity of mesalazine most likely depends on a local contact of the drug with the diseased area of the intestinal mucosa.
Pentasa suppositories and rectal suspensions are designed to provide the distal part of the intestinal tract with high concentrations of mesalazine and a low systematic absorption. Suppositories cover the rectum, whereas rectal suspensions have been shown to reach and cover the descending colon.
The absorption following rectal administration is low, and depends on the dose, the formulation and the extent of spread. Based on urine recoveries in healthy volunteers under steady-state conditions given a daily dose of 2 g (1 g x 2), approximately 10% of the dose is adsorbed after administration of suppositories whereas about 15-20% is absorbed after administration of rectal suspensions.
Mesalazine and acetyl mesalazine do not cross the blood-brain barrier. Protein binding of mesalazine is approximately 50% and of acetyl mesalazine about 80%
Mesalazine is metabolised both pre-systemically by the intestinal mucosa and systemically in the liver to N-acetyl-mesalazine (acetyl-mesalazine) principally by NAT-1.
Some acetylation also occurs through the action of colonic bacteria. The acetylation seems to be independent of the acetylator phenotype of the patient. The metabolic ratio of acetyl-mesalazine to mesalazine in plasma after oral administration ranges from 3.5 to 1.3 after daily doses of 500 mg×3 and 2 g×3, respectively, implying a dose-dependent acetylation which may be subject to saturation.
Due to continuous release of mesalazine from Pentasa throughout the gastrointestinal tract, the elimination half-life cannot be determined after oral administration. However, once the formulation is not present in the GI tract elimination will follow the plasma half-life of orally or iv administered uncoated mesalazine, which is approximately 40 minutes and for acetyl-mesalazine approximately 70 minutes.
Pathophysiologic changes such as diarrhoea and increased bowel activity observed during active inflammatory bowel disease has only a minor impact on the delivery of mesalazine to the intestinal mucosa after oral administration. A urine excretion 20–25% of the daily dose has been observed in patients with accelerated intestinal transit. Likewise a corresponding increase in faecal excretion has been seen.
Toxic renal effects have been demonstrated in all species tested. Rat and monkey dosages and plasma concentrations at the No Observed Adverse Effect Levels (NOAELs) exceed those used in humans by a factor of 2-7.2. No significant toxicity associated with the gastrointestinal tract, liver or haematopoietic system in animals has been observed.
In-vitro test systems and in-vivo studies showed no evidence of mutagenic effects. Studies on the tumourigenic potential carried out in rats showed no evidence of any substance-related increase in the incidence of tumours.
Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to fertility, pregnancy, embryo-foetal development, parturition or postnatal development.
Mesalazine is deemed not to pose a risk to the environment at the doses prescribed for use in patients.
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