PENTASA^® Mesalazine Enema.

Each enema bottle contains mesalazine 1g in 100ml.

Rectal suspension.

Each bottle contains 100ml of a colourless to faint yellow suspension containing 1g mesalazine

PENTASA Mesalazine Enema is indicated for the treatment of ulcerative colitis affecting the distal colon and rectum.

Adults: The recommended dosage is one enema at bedtime.

Children: Not recommended.

PENTASA Mesalazine Enemas are for rectal administration

PENTASA is contraindicated in:

- patients with known sensitivity to salicylates

- patients with severe liver and/or renal impairment

- patients allergic to any of the ingredients

Serious blood dyscrasias have been reported rarely with mesalazine. Haematological investigations should be performed if the patient develops unexplained bleeding, bruising, purpura, anaemia, fever or sore throat. Treatment should be stopped if there is suspicion or evidence of blood dyscrasia.

Most patients who are intolerant or hypersensitive to sulphasalazine are able to use 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.

It is recommended that mesalazine is used with extreme caution in patients with mild to moderate renal impairment (see section 4.3).

If a patient develops dehydration while on treatment with mesalazine, normal electrolyte levels and fluid balance should be restored as soon as possible.

Mesalazine induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported rarely. Treatment should be discontinued on suspicion or evidence of these reactions.

The concurrent use of mesalazine with other known nephrotoxic agents, such as NSAIDs and azathioprine, may increase the risk of renal reactions (see section 4.4).

Concomitant treatment with mesalazine can increase the risk of blood dyscrasia in patients receiving azathioprine or 6-mercaptopurine.

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

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

Blood disorders (leucopenia, thrombocytopenia, anaemia) have been reported in new-borns of mothers being treated with PENTASA.

Mesalazine is excreted in breast milk. The mesalazine concentration in breast milk is lower than in maternal blood, whereas the metabolite, acetyl mesalazine appears in similar or increased concentrations. There is limited experience of the use of oral mesalazine in lactating women. No controlled studies with PENTASA during breast-feeding have been carried out. Hypersensitivity reactions like diarrhoea in the infant cannot be excluded.

No adverse effects.

Mesalazine may be associated with an exacerbation of the symptoms of colitis in those patients who have previously had such problems with sulphasalazine.

Undesirable effects are as follows:

*Renal failure has been reported. Mesalazine-induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment.

The mechanism of mesalazine induced myocarditis, pericarditis, pancreatitis, nephritis and hepatitis is unknown, but it might be of allergic origin.

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

Acute experience in animals:

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

Human experience:

No cases of overdose have been reported.

Management of overdose in man:

Symptomatic treatment at hospital. Close monitoring of renal function. Intravenous infusion of electrolytes may be used to promote diuresis.

Pharmacotherapeutic group: Intestinal anti-inflammatory agents.

Mechanism of action and pharmacodynamic effects:

Mesalazine is recognised as the active moiety of sulphasalazine in the treatment of ulcerative colitis. It is thought to act locally on the gut wall in inflammatory bowel disease, although its precise mechanism of action has not been fully elucidated.

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. 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.

General characteristics of the active substance

Disposition and local availability:

PENTASA enemas are designed to provide the distal part of the intestinal tract with high concentrations of mesalazine and a low systemic absorption. The 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). The acetylation seems to be independent of the acetylator phenotype of the patient. Some acetylation also occurs through the action of colonic bacteria.

Acetyl mesalazine is thought to be clinically as well as toxicologically inactive, although this remains to be confirmed.

Absorption:

The absorption following rectal administration is low, but 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 2g (1g x 2), about 15-20% of the dose 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%.

Elimination:

The plasma half-life of pure mesalazine is approximately 40 minutes and for acetyl mesalazine approximately 70 minutes. Both substances are excreted in urine and faeces. The urinary excretion consists mainly of acetyl mesalazine.

Characteristics in patients:

The systematic absorption following administration of PENTASA enemas has been shown to be significantly decreased in patients with active ulcerative colitis 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.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Disodium edetate

Sodium metabisulphite

Sodium acetate

Hydrochloric acid, concentrated

Purified water

None known.

24 months.

Do not store above 25ºC. Keep bottle in the outer carton.

Polyethylene enema bottles fitted with a tip and valve for rectal application, supplied in nitrogen-filled aluminium-foil bags. Presented in cartons containing 7 x 100ml bottles individually foil-wrapped.

None.

Ferring Pharmaceuticals Ltd.,

The Courtyard

Waterside Drive

Langley

Berkshire SL3 6EZ.

PL 3194/0027

4^th February 2004

February 2005

POM