Pentasa 10 mg/ml Rectal Suspension

Each bottle of rectal suspension contains mesalazine 1g in 100ml.

For a full list of excipients, see section 6.1.

Rectal suspension

White to slightly yellow suspension

Pentasa Rectal Suspension is indicated in the management of active ulcerative colitis.

Adults:

The recommended dosage is 1g mesalazine (100ml Rectal Suspension) at bedtime for 2 − 3 weeks.

Children:

Reduced dose based on body weight.

Most patients who are intolerant or hypersensitive to sulphasalazine 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. Liver function parameters like ALT or AST should be assessed prior to and during treatment, at the discretion of the treating physician.

The drug is not recommended for use in patients with renal impairment. The renal function should be monitored regularly (e.g. serum creatinine), especially during the initial phase of treatment. Mesalazine induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment. The concurrent use of other known nephrotoxic agents should increase monitoring frequency of renal function.

Mesalazine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported rarely. Serious blood dyscrasias have been reported rarely with mesalazine. Blood test for differential blood count is recommended prior to and during treatment, at the discretion of the treating physician. As stated in the interaction section 4.5, concomitant treatment with mesalazine can increase the risk of blood dyscrasia in patients receiving azathioprine or 6-mercaptopurine. Treatment should be discontinued on suspicion or evidence of these adverse reactions.

Combination therapy with PENTASA and azathioprine or 6-mercaptopurine have in several studies shown a higher frequency of leucopenia, and an interaction seems to exist, however, the mechanism behind the interaction is not fully established. Regular monitoring of white blood cells is recommended and dosage regime of thiopurines should be adjusted accordingly.

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 and its concentration in umbilical cord plasma is one tenth of the concentration in maternal plasma. The metabolite acetyl-mesalazine is found in the same concentration in umbilican cord and maternal plasma. From several observational studies no teratogenic effects are reported and there is no evidence of significant risk of use in humans. In animal studies no teratogenic or mutagenic effects have been observed.

Blood disorders (pancytopenia, 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 can not be excluded.

No adverse effects.

The most frequent adverse reactions seen in clinical trials are diarrhoea nausea abdominal pain, headache, vomiting and rash. Hypersensitivity reactions and drug fever may occasionally occur. Following rectal administration, local reactions such as pruritus, rectal discomfort and urge may occur.

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

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

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:

There is limited clinical experience with overdose of PENTASA.

There have been reports of patients taking daily doses of 8 grams for a month without any adverse events.

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 (A07 EC02).

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 Rectal Suspension are designed to provide the distal part of the intestinal tract with high concentrations of mesalazine and a low systemic absorption. The Rectal Suspension has 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, 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 2g (1g × 2), about 15−20% of the dose is absorbed after administration of Rectal Suspensions.

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 mesalazine following i.v. administration 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 Rectal Suspension 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.

Definitive nephrotoxicity and possible gastrointestinal toxicity is demonstrated in all species examined, and nephrotoxicity is evident with doses 5−10 times those used in humans.

In−vitro test systems and in−vivo studies showed no evidence of mutagenic effects. Studies on the tumorigenic potential carried out in rats showed no evidence of any substance−related increase in the incidence of tumours.

Disodium edetate.

Sodium metabisulfite (E223)

Sodium acetate.

Hydrochloric acid (for pH adjustment)

Purified water.

Not applicable.

Before opening individual foil pack: 3 years

After opening individual foil pack: Use immediately

Do not store above 25°C. Store in the original package to protect from light.

Polyethylene Rectal Suspension bottle wrapped in aluminium foil bags. Presented in cartons containing 7 × 100ml bottles individually foil−wrapped. A plastic sleeve bearing administration instructions is provided for each Rectal Suspension bottle. The sleeve also facilitates hygienic application of the Rectal Suspension and disposal after use.

Shake the Rectal Suspension bottle well before use.

Ferring Ireland Ltd.,

United Drug House,

Magna Drive,

Magna Business Park,

Citywest Road,

Dublin 24,

Ireland

PA 1009/6/3

April 2010