PENTASA Sachet 1g prolonged release granules

Each sachet contains mesalazine 1 g

For a full list of excipients, see section 6.1.

Prolonged release granules

White-grey to pale white-brown granules

Mild to moderate ulcerative colitis

Ulcerative colitis

Adults

Active disease

Individual dosage, up to 4 g mesalazine daily divided into 2-4 doses.

Maintenance treatment

Individual dosage. Recommended dosage, 2 g mesalazine once daily.

Paediatric population:

There is only limited documentation for an effect in children (age 6-18 years).

Children 6 years of age and older:

Active disease: To be determined individually, starting with 30-50 mg/kg/day in divided doses. Maximum dose: 75 mg/kg/day in divided doses. The total dose should not exceed 4 g/day (maximum adult dose).

Maintenance treatment: To be determined individually, starting with 15-30 mg/kg/day in divided doses. The total dose should not exceed 2 g/day (recommended adult dose).

It is generally recommended that half the adult dose may be given to children up to a body weight of 40 kg; and the normal adult dose to those above 40 kg.

The granules must not be chewed.

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

Hypersensitivity to mesalazine, any other component of the product, or salicylates.

Severe liver and/or renal impairment.

Caution is recommended when treating patients allergic to sulphasalazine (risk of allergy to salicylates). In case of acute symptoms of intolerance, i.e. cramps, abdominal pain, fever, severe headache and rash, the treatment should be discontinued immediately.

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

Blood tests (differential blood count; liver function parameters like ALT or AST) should be assessed prior to and during treatment, at the discretion of the treating physician.

The concurrent use of other known nephrotoxic agents, such as NSAIDs and azathioprine, may increase the risk of renal reactions.

Caution is recommended in patients with active peptic ulcer.

Mesalazine-induced cardiac hypersensitivity reactions (myo- and pericarditis) have been reported rarely. Serious blood dyscrasias have been reported very rarely with mesalazine (see section 4.5). Treatment should be discontinued on suspicion or evidence of these adverse reactions.

No specific interaction studies have been performed. Concomitant treatment with mesalazine can increase the risk of blood dyscrasia in patients receiving azathioprine or 6-mercaptopurine.

PENTASA Sachet should not be used during pregnancy and lactation except when the potential benefits of the treatment outweigh the possible hazards in the opinion of the physician.

Pregnancy:

Mesalazine is known to cross the placental barrier. The limited data available on the use of this compound in pregnant women do not allow assessment of possible adverse effects. No teratogenic effects have been observed in animal studies and in a controlled human study.

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

Lactation:

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. No controlled studies with PENTASA during breast-feeding have been carried out. Only limited experience during lactation in women after oral application is available to date. Hypersensitivity reactions like diarrhoea can not be excluded.

None known.

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 and drug fever may occasionally occur

Frequency of adverse effects, based on clinical trials and reports from post-marketing surveillance

(*) The mechanism of mesalazine-induced myo- and 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 the inflammatory bowel disease itself.

Experience in animals:

A single intravenous dose of mesalazine in rats of 920 mg/kg and single oral doses of mesalazine in pigs up to 5g/kg were not lethal.

Human experience:

No experience

Management of overdose in man:

Symptomatic treatment at hospital. Close monitoring of renal function.

Pharmacotherapeutic group : Intestinal anti-inflammatory agents

ATC-Code: A07E C02

Mesalazine is the active component of sulphasalazine, which has been used for a long time in the treatment of ulcerative colitis and Crohn's disease.

The therapeutic value of mesalazine 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 inflammatory bowel disease. Mesalazine has in-vitro and in-vivo pharmacological effects that inhibit leukocyte chemotaxis, decrease cytokine and leukotriene production and scavenge for free radicals. The mechanism of action of mesalazine is, however, still not understood.

General characteristics of the active substance

PENTASA Sachet prolonged release granules consist of ethylcellulose coated microgranules of mesalazine. Following administration mesalazine is released continuously throughout the gastrointestinal tract in any enteral pH conditions. The microgranuales enter the duodenum within an hour of administration, independent of food co-administration. The average small intestinal transit time is approximately 3 – 4 hrs in healthy volunteers.

Biotransformation:

Mesalazine is metabolised into N-acetyl-mesalazine (acetyl mesalazine) both pre-systematically by the intestinal mucosa and systemically in the liver. Some acetylation also occurs through the action of colonic bacteria. The acetylation seems to be independent of the acetylator phenotype of the patient. Acetyl-mesalazine is believed to be clinically as well as toxicologically inactive.

Absorption:

30-50% of an oral dose is absorbed, predominantly from the small intestine. Maximum plasma concentrations are seen 1-4 hours post-dose. The plasma concentration of mesalazine decreases gradually and is no longer detectable 12 hours post-dose. The plasma concentration curve for acetyl-mesalazine follows the same pattern, but the concentration is 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 daily doses of 500mg x 3 and 2g x 3, respectively, implying a dose-dependent acetylation which may be subject to saturation.

Mean steady-state plasma concentrations of mesalazine are approximately 2µmol/l, 8µmol/l and 12µmol/l after 1.5g, 4g and 6g daily dosages, respectively. For acetyl-mesalazine the corresponding concentrations are 6µmol/1, 13µmol/1 and 16µmol/1.

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

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 following i.v. administration of mesalazine is approximately 40 minutes and for acetyl-mesalazine approximately 70 minutes. Due to the continuous release of mesalazine throughout the gastrointestinal tract, the elimination half-life cannot be determined after oral administration. Tests have shown that steady-state is reached after a treatment period of 5 days following oral administration.

Both mesalazine and acetyl-mesalazine are excreted with the urine and faeces. The urinary excretion consists mainly of acetyl-mesalazine.

Characteristics in patients

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

In patients with impaired liver and kidney functions, the resultant decrease in the rate of elimination 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 tumourigenic potential carried out in rats showed no evidence of any substance-related increase in the incidence of tumours.

Ethylcellulose, povidone

Not applicable

2 years

The granules should be used immediately after first opening of the sachet.

This medicinal product does not require any special storage conditions.

Aluminium foil single dose container

Pack sizes:

1 x 50 sachets

2 x 50 or 100 sachets

3 x 50 or 150 sachets

Not all pack sizes may be marketed

Any unused product or waste material should be disposed of in accordance with local requirements.

Ferring Pharmaceuticals Ltd

The Courtyard

Waterside Drive

Langley

Berkshire SL3 6EZ.

United Kingdom

PL 03194/0075

5^th December 2007

7^th April 2010