PENTASA

mesalazine

Presentation

Slow release tablet 250mg: white to light grey speckled tablet with a break-mark, containing 250mg mesalazine (5-aminosalicylic acid). Length 12mm, average weight 500mg.

Slow release tablet 500mg: round, white to light grey speckled tablet with a break-mark on one side and the inscription gbr212 on the other, and containing 500mg mesalazine (5-aminosalicylic acid). Diameter 13.6mm ave, weight approx. 750mg.

Enema: a colourless to slightly yellow suspension containing 10mg/ml mesalazine (5-aminosalicylic acid) in purified water. Added buffering agents result is a slightly acidic suspension. Sodium metabisulphite is added as a antioxidant.

Suppository: a white to light tan spotted oblong compressed suppository, average weight 1580mg, 1cm diameter and 2.8cm long. Contains 1000mg mesalazine.

Granules, prolonged-release: white to pale brown, round granules, containing 1000mg mesalazine.

Uses

Actions

It has been established that mesalazine is the active component of sulfasalazine, which is used for the treatment of colitis ulcerosa 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.

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 IBD. Mesalazine has in vitro and in vivo pharmacologic effects that inhibit leucocyte chemotaxis, decrease cytokine and leucotriene 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.

Pharmacokinetics

General characteristics of the active substance

Disposition and local availability

The therapeutic activity of mesalazine most likely depends on a local contact of the medicine with the diseased area of the intestinal mucosa.

PENTASA prolonged-release granules and tablets consist of ethylcellulose-coated microgranules of mesalazine. Following administration and tablet disintegration the microgranules act as discrete prolonged-release formulations which allow a continuous release of medicine from duodenum to rectum at all enteral pH conditions.

The microgranules arrive in the duodenum within 1 hour after administration, independently of food co-administration. The average small intestinal transit time is approximately 3-4 hours, whereas the transit through the colon is approximately 8 hours in healthy volunteers.

PENTASA suppositories and enemas are designed to provide the distal part of the intestinal tract with high concentrations of mesalazine and a low systemic absorption. Suppositories cover the rectum, whereas enemas have been shown to reach and cover the descending colon.

Biotransformation

Mesalazine is metabolised both pre-systemically by the intestinal mucosa and systemically in the liver to N-acetyl-mesalazine (acetyl-mesalazine). Some acetylation also takes place by colonic bacteria. The acetylation seems to be independent of the acetylator phenotype of the patient.

Acetyl-mesalazine is thought to be clinically as well as toxicologically inactive, but this still needs final confirmation.

Absorption

Based on urine recovery data in healthy volunteers, 30-50% of the ingested dose will be absorbed following oral administration, predominantly from the small intestine.

Mesalazine is detectable in plasma already 15 minutes following administration. Maximum plasma concentrations are seen 1-4 hours post-dose. After a gradual decrease, mesalazine will no longer be detectable 12 hours post-dose. The plasma concentration curve for acetyl-mesalazine follows the same pattern, but the concentrations are generally higher and the elimination is slower.

The metabolic ratio of acetyl-mesalazine to mesalazine in plasma after oral administration ranges from 3.5 to 1.3 after 500mgx3 and 2gx3 dosages, respectively, implying a saturable dose-dependent acetylation.

Mean steady-state plasma concentrations of mesalazine are approximately 2 micromol/l, 8 micromol/l and 12 micromol/l after 1.5g, 4g and 6g daily dosages, respectively. For acetyl-mesalazine the corresponding concentrations are 6 micromol/l, 13 micromol/l and 16 micromol/l.

The transit and release of mesalazine after oral administration are independent of food co-administration, whereas the systemic absorption will be reduced.

The absorption following rectal administration is low, but depends on the dose, the formulation and the extent of spreading. Based on urine recoveries in healthy volunteers under steady-state conditions given a daily dose of 2g (1g x 2), approximately 10% of the dose is absorbed after administration of suppositories whereas about 15-20% is absorbed after administration of enemas.

Distribution

Mesalazine and acetyl-mesalazine do not cross the blood-brain barrier. Protein binding of mesalazine is approximately 50% and of acetyl-mesalazine about 80%.

The plasma half-life of pure mesalazine is approximately 40 minutes and for acetyl-mesalazine approximately 70 minutes. Due to the continuous release of mesalazine from PENTASA throughout the gastrointestinal tract, the elimination half-life cannot be determined after oral administration. However, steady-state is reached after a treatment period of 5 days following tablet administration.

Both substances are excreted with the urine and faeces.

The urinary excretion consists mainly of acetyl-mesalazine.

Characteristics in patients

The delivery of mesalazine after oral administration is only slightly affected by the pathophysiologic changes observed during active inflammatory bowel disease such as diarrhoea and increased bowel acidity. A reduction in systemic absorption to 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.

The systemic absorption following administration of PENTASA enemas has been shown to be significantly decreased in patients with active ulcerative colitis as compared to those in remission.

In patients with impaired liver and kidney functions, the resultant decrease in the rate of elimination and increased systemic concentration of mesalazine may constitute an increased risk of nephrotoxic adverse reactions.

Indications

Slow release tablets 250mg, 500mg and prolonged-release granules 1g:

Treatment of mild to moderate ulcerative colitis or Crohn's disease.

Enemas:

Left-sided ulcerative colitis, proctitis.

Suppositories:

Treatment of ulcerative proctitis.

Dosage And Administration

Slow Release Tablets 250mg, 500mg/Prolonged Release Granules 1g

Ulcerative colitis

Adults: Individual dosage, up to 4g daily in divided doses.

Children: Individual dosage, starting with 20-30mg/kg bodyweight daily in divided doses.

Adults: Individual dosage, starting with 1.5-2g daily in divided doses.

Children: Individual dosage, starting with 20-30mg/kg bodyweight daily in divided doses.

Crohn's disease

Adults: Individual dosage, up to 4g daily in divided doses.

Children: Individual dosage, starting with 20-30mg/kg bodyweight daily in divided doses.

Adults: Individual dosage, up to 4g daily in divided doses.

Children: Individual dosage, starting with 20-30mg/kg bodyweight daily in divided doses.

PENTASA tablets or granules must not be chewed.

The contents of the PENTASA granules sachet should be emptied onto the tongue and washed down with some water or orange juice.

Enema

Shake bottle immediately before use.

Adults: 1g mesalazine (5-ASA) (100ml enema) at bedtime for 2-3 weeks.

Children: Reduced dose based on body weight. Generally, 10-20mg/kg body weight per day.

Topical treatment can also be administered as maintenance treatment.

Suppository

The dosage should be adapted to the severity of the disorder. For adults and older children it is generally recommended: 1 suppository 1-2 times daily .

Contraindications

Hypersensitivity to mesalazine, any other component of the product, or salicylates. Severe liver and/or renal impairment.

Warnings and Precautions

Most patients who are intolerant or hypersensitive to sulfasalazine are able to take PENTASA without risk of similar reactions. However, caution is recommended when treating patients allergic to sulphasalazine (risk of allergy to salicylates).

Caution is recommended in patients with impaired liver function. The medicine is not recommended for use in patients with renal impairment. Mesalazine-induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment. The renal function should be regularly monitored (e.g. serum creatinine), especially during the initial phase of treatment.

Mesalazine-induced cardiac hypersensitivity reactions (myo- and pericarditis) and serious blood dyscrasias have rarely been reported with mesalazine. Treatment should be discontinued on suspicion or evidence of these adverse reactions.

PENTASA should be used with caution during pregnancy and lactation and only if the potential benefits outweigh the possible hazards in the opinion of the physician.

Mesalazine is known to cross the placental barrier, but the limited data available on the use of this compound in pregnant women do not allow to assess possible noxious effects. No teratogenic effects have been observed in animal studies.

Mesalazine is excreted in breast milk. The concentration is much lower than in maternal blood, whereas the metabolite - acetyl-mesalazine - appears in similar concentrations. No adverse effects in suckling babies of mothers treated with PENTASA have been reported, but the data available are very limited.

Treatment with PENTASA is unlikely to affect the ability to drive and/or use machines.

Adverse Effects

The most frequent adverse reactions seen in clinical trials are diarrhoea (3%), nausea (3%), abdominal pain (3%), headache (3%), vomiting (1%) and rash (1%). Hypersensitivity reactions may occasionally occur.

Following rectal administration local reactions such as pruritus, rectal discomfort and urge may occur.

(*) The mechanism of mesalazine-induced myo- and pericarditis, pancreatitis, nephritis and hepatitis is unknown, but it might be of an allergic origin.

It is important to note that several of these disorders also can be attributed to the inflammatory bowel disease itself.

Interactions

There are no data on interactions between PENTASA and other medicines.

Overdosage

Single oral doses of mesalazine up to 5g/kg in pigs or a single intravenous dose of mesalazine at 920mg/kg in rats were not lethal.

No cases of overdose have been reported.

Symptomatic treatment at hospital. Close monitoring of renal function. Haemodialysis may be considered.

Pharmaceutical Precautions

Storage at room temperature (15-25°C) in original packaging.

Shelf-Life

Slow-release tablets 250mg and 500mg:

3 years in original packaging.

Prolonged-release granules 1g:

2 years in original packaging.

Suppositories:

2 years in original packaging.

Enemas:

3 years in original packaging.

Medicine Classification

Prescription Medicine.

Package Quantities

PENTASA slow release tablets 250mg and 500mg double aluminium foil blisters of 10 tablets - boxes of 10 strips.

PENTASA prolonged-release granules 1g - individually packed sachets of aluminium foil.

PENTASA enemas 10mg/ml - 100mls, boxes of 7x100mls.

PENTASA suppositories 1gm - boxes of 2, 4 or 8 double aluminium foil blisters, each containing 7 suppositories.

Instructions For Use/Handling

The enemas are protected by an aluminium foil bag and should be used immediately after opening.

A visit to the toilet is recommended before administration of suppositories and enemas. See separate instructions for use.

Further Information

The kidney appears to be the major target for mesalazine toxicity in animal studies. A dose-dependent nephrotoxic effect has been demonstrated in subchronic and chronic studies in mice, rats, rabbits and monkeys. The toxicity primarily affects the glomeruli and tubules, typically at daily doses 5-15 times higher than the therapeutic dose in humans. However, in rats minor kidney changes beginning at therapeutic doses have been reported in some studies (slightly increased creatinine, hypercellularity of the glomeruli).

No significant toxicity associated with the gastrointestinal tract, liver, or haematopoietic system in animals has been observed.

None known.