SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Mesalazine NORDIC 2 g granules for rectal suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Mesalazine NORDIC 2 g granules for rectal suspension contains 2 g mesalazine per sachet

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Granules for rectal suspension

Almost white to light grey to light pink or pale brown granules

4    CLINICAL PARTICULARS

Mesalazine NORDIC granules for rectal suspension is indicated for the treatment of mild to moderate left-sided ulcerative colitis (UC).

4.1    Therapeutic indications

Mesalazine NORDIC granules for rectal suspension is indicated for the treatment of mild to moderate left-sided ulcerative colitis (UC).

4.2    Posology and method of administration

Route of administration: Rectal

Dose recommendation

Adults:

Mesalazine NORDIC 2 g

Maintainence phase: 1 time a day at bedtime

Children:

There is no dosage recommendation

The lowest dose possible should be used to maintain remission.

For instructions on preparation of the medicinal product before administration, see section 6.6.

Contraindications

-    Patients with hypersensitivity to mesalazine, or to any of the excipients listed in section 6.1, or salicylates

-    Patients with severe liver and/or renal impairment

4.4 Special warnings and precautions for use

Blood tests (differential blood count; liver function parameters such as ALT or AST; serum creatinine) and urinary status (dip sticks) should be determined prior to and during treatment, at the discretion of the treating physician. As a guideline, follow-up tests are recommended 14 days after commencement of treatment, then a further two to three tests at intervals of 4 weeks.

If the findings are normal, follow-up tests should be carried out every three months. If additional symptoms occur, these tests should be performed immediately. 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.

Caution is recommended when treating patients allergic to sulphasalazine (risk of allergy to salicylates).

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 cardiovascular toxicity, including pericarditis, myocarditis, vasculitis, and left ventricular dysfunction have been reported rarely. Treatment should be discontinued on suspicion or evidence of these reactions.

Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment with Mesalazine NORDIC.

Renal and/or liver impairment

Mesalazine should be is used with extreme caution in patients with mild to moderate renal impairment (see section 4.3 and 4.8). Mesalazine-induced nephrotoxicity may occur. Renal function (serum creatinine) should therefore be determined prior to and also regularly during Mesalazine treatment.

Caution is required in patients with impaired liver function (see section 4.3 and 4.8)

4.5 Interaction with other medicinal products and other forms of interaction

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

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

There are limited indications that mesalazine decreases the anticoagulant effects of warfarin.

4.6 Fertility, pregnancy and lactation

Pregnancy:

Mesalazine is known to cross the placental barrier. Data on a limited number of exposed pregnancies indicate no adverse effect of mesalazine on the pregnancy or on the health of the fetus/newborn child. To date no other relevant epidemiologic data are available. Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/fetal development, parturition or postnatal development.

Mesalazine should only be used during pregnancy if the potential benefit outweighs the possible risk..

Breast-feeding:

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. Hypersensitivity reactions such as diarrhoea in the infant cannot be excluded. Therefore, Mesalazine NORDIC should only be used during breast-feeding, if the potential benefit outweighs the possible risk. If the infant develops diarrhoea, breast-feeding should be discontinued.

Fertility:

Animal data on Mesalazine show no effect on male and female fertility

4.7    Effects on ability to drive and use machines

Mesalazine NORDIC granules for rectal suspension has no or negligible influence on the ability to drive or use machines.

4.8    Undesirable effects

List of adverse reactions

The following headings are used to rank the adverse reactions by frequency: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

Undesirable effects are as follows:

System Organ Class	Very Common	Common	Uncommon	Rare	Very Rare
Blood and Lymphatic System Disorders					altered blood counts (aplastic anaemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia)
Immune System Disorders					hypersensitivity reactions
Nervous System Disorders				headaches, dizziness	peripheral neuropathy
Cardiac Disorders				myocarditis, pericarditis, vasculitis, left ventricular dysfunction
Respiratory, Thoracic and Mediastinal Disorders					allergic lung reactions (including dyspnoea, coughing, allergic alveolitis, pulmonary eosinophilia, pulmonary infiltration, pneumonitis)
Gastrointestinal Disorders				nausea, vomiting, diarrhoea, abdominal pain	acute pancreatitis,
Hepatobiliary Disorders					abnormalities of hepatic function and hepatotoxicity (including hepatitis, cirrhosis, hepatic failure), increased liver enzymes and bilirubin
Skin and Subcutaneous Tissue Disorders		rash (including urticaria and erythemato us rash)		bullous skin reactions including erythema multiforme and Stevens-Johnson syndrome	reversible alopecia
Musculoskeletal and Connective Tissue Disorders			lupus erythematos us-like reactions		myalgia, arthralgia
Renal and Urinary Disorders*					abnormal renal function (including interstitial nephritis, nephrotic syndrome), urine discolouration
General Disorders and Administration Site Conditions
Reproductive system disorders					Oligospermia (reversible)
* Mesalazine-induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment. See section 4.3, 4.4 and 4.5.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal

product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/vellowcard.

4.9 Overdose

No cases of overdose with mesalazine enemas have been reported.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic groups: Intestinal anti-inflammatory agents, aminosalicylic acid and similar agents

ATC code: A07E C02

Mesalazine's mechanism of action in UC is unclear, but it appears to act topical on the damaged epithelium cells of the intestine rather than systemic.

The proposed mechanisms of anti-inflammatory action of mesalazine currently include the inhibition of cyclooxygenase and lipoxygenase pathways, thus reducing production of prostaglandins and leukotrienes, respectively, and the reversion of the antiproliferative effects of tumour necrosis factor a (TNFa), resulting in the disruption of the effect of cytokines by reducing intestinal cell transcription of inflammatory mediators.

Another proposed mechanism of action of mesalazine is via inhibition of interleukine 2 (IL-2) production in peripheral mononuclear cells and thereby inhibiting T-cell proliferation, altering cell adhesion expression pattern, inhibiting antibody production and mast cell release, and interfering with macrophage and neutrophil chemotaxis.

5.2    Pharmacokinetic properties

The enema is intended to deliver mesalazine directly to the proposed site of action in the colon and rectum.

Disposition and local availability

Mesalazine granules for rectal suspension are designed to provide the distal part of the intestinal tract with high concentrations of mesalazine.

Absorption and Bioavailability

Mesalazine undergoes N-acetylation in intestinal mucosa and liver. The main metabolite, N-acetylmesalazine, is not thought to have anti-inflammatory activity.

Distribution and Metabolism

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

Mesalazine that is absorbed undergoes N-acetylation in the intestinal mucosa and liver and is excreted into urine as a mixture of metabolized and parent drug.

5.3 Preclinical safety data

Animal studies have only revealed effects at exposures much in excess of those expected in humans, and are therefore not considered relevant.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Xanthan gum Crosscarmellose sodium Sodium chloride

6.2    Incompatibilities

Not applicable

6.3    Shelf life

15 months

6.4    Special precautions for storage

Store below 30°C in the original packaging in order to protect from light.

6.5 Nature and contents of container

Nature of container:

Aluminium foil sachet

Polyethylene enema bottles fitted with a tip and valve for rectal enema preparation and application.

Pack sizes:

Sachets containing 2 g individual doses and enema bottles in packs of 7 and 14. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

Prior to use dispense the content from the sachet(s) into the enema bottle. Fill the enema bottle up to the mark with tap water or drinkable still water, shake for 30 seconds. After 5 minutes shake for a further 30 seconds. Use immediately.

7 MARKETING AUTHORISATION HOLDER

Nordic Group B.V.

Siriusdreef 22 2132 WT Hoofddorp The Netherlands

8    MARKETING AUTHORISATION NUMBER(S)

PL 40621/0002

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

10 DATE OF REVISION OF THE TEXT