Pentasa 1 g Prolonged-release Tablets

Each tablet contains mesalazine, 1 g.

For full list of excipients, see section 6.1.

Prolonged-release tablet.

White-grey to pale brown, speckled, oval tablet. Embossing on both sides: PENTASA

For the treatment of Ulcerative colitis and Crohn's disease.

Ulcerative Colitis

Adults:

Acute Treatment: Individual dosage, up to 4 g mesalazine daily in divided doses.

Maintenance treatment: Recommended dosage, 2 g mesalazine once daily.

Children:

Individual dosage, recommended starting dose is 20-30 mg/kg bodyweight daily in divided doses.

Crohn's Disease

Adults:

Acute Treatment: Individual dosage, up to 4 g mesalazine daily in divided doses.

Maintenance treatment: Individual dosage, up to 4 g mesalazine daily in divided doses.

Children:

Individual dosage, recommended starting dose is 20-30 mg/kg bodyweight daily in divided doses.

Pentasa tablets must not be chewed. To facilitate swallowing the tablets may be dispersed in 50 ml of cold water. Stir and drink immediately.

Hypersensitivity to mesalazine , any of the excipients, or salicylates

Severe liver and/or renal impairment

Children under the age of 2 years

Active peptic ulcer

Coagulopathy

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 very 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 benefits outweigh 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 umbilical 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.

* 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.

ATC Code: 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 tablets consist of ethylcellulose-coated microgranules of mesalazine. Following administration and tablet disintegration the microgranules act as discrete slow-release formulations which allow a continuous release of drug from duodenum to rectum at all enteral pH conditions. The microgranules enter the duodenum within an hour of administration, independent of food co-administration. In healthy volunteers the average small intestinal transit time is approximately 3-4 hours.

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: Based on urinary recovery data in healthy volunteers, 30-50% of the ingested dose is absorbed following oral administration, predominantly from the small intestine. Mesalazine is detectable in plasma approximately 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 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 2 micromoles /l, 8 micromoles/l and 12 micromoles/l after daily doses of 1.5g, 4g and 6g respectively. For acetyl mesalazine the corresponding concentrations are 6 micromoles/l 13 micromoles/l and 16 micromoles/l respectively.

The transit and release of mesalazine after oral administration are independent of food co-administration, whereas the systemic absorption is 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 of pure mesalazine is approximately 40 minutes and for acetyl mesalazine approximately 70 minutes. Due to 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 oral administration. Both substances are excreted in urine and faeces. The urinary excretion consists mainly of acetyl mesalazine.

Characteristics in patients:

The delivery of mesalazine to its site of action after oral administration is only slightly affected by pathophysiological changes such as diarrhoea and increased bowel activity 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. 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 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.

Povidone

Ethylcellulose

Magnesium Stearate

Talc

Microcrystalline Cellulose

Not applicable

3 years

Do not store above 25°C. Store in the original package, as the product is sensitive to light.

Double aluminium foil blisters, containing 60 tablets, presented in cardboard cartons.

No special requirements

Ferring Ireland Limited

United Drug House

Magna Drive

Magna Business Park

Citywest Road

Dublin 24

Ireland

PA 1009/6/7

7^th January 2011