4.1. Therapeutic indications

Mild to moderate ulcerative colitis

4.2. Posology and method of administration

Posology

Ulcerative colitis

Adults

Active disease

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

Maintenance treatment

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

Paediatric population:

The safety and efficacy in children below 6 years of age have not been established.

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 once daily or in divided doses. Maximum dose: 75 mg/kg/day once daily or 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 once daily or 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.

Method of administration

Oral use

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. Alternatively, the entire content of the sachet can be taken with yogurt and consumed immediately.

4.3. Contraindications

Hypersensitivity to mesalazine, any of the excipients, or salicylates.

Severe liver and/or renal impairment.

4.4. Special warnings and precautions for use

Caution is recommended when treating patients allergic to sulphasalazine (risk of allergy to salicylates). Severe cutaneous adverse reactions (SCARs), including Drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment. In case of acute symptoms of intolerance, i.e. abdominal cramps, abdominal pain, fever and severe headache, and/or the first appearance of signs and symptoms of severe skin reactions, such as skin rash, mucosal lesions, or any other signs of hypersensitivity, the treatment should be discontinued immediately.

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.

Renal impairment

The drug is not recommended for use in patients with impaired renal function and in patients with haemorrhagic diathesis. The renal function should be regularly monitored (e.g. serum creatinine), especially during the initial phase of treatment. Urinary status (dip sticks) should be determined prior to and during treatment at the discretion of the treating physician. Mesalazine induced nephrotoxicity should be suspected in patients developing renal dysfunction during treatment. Mesalazine treatment should be discontinued immediately if renal function deteriorates. 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.

Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment; please refer to section 4.8.

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). Blood tests for differential blood counts is recommended prior to and during treatment, at the discretion of the treating physician. Treatment should be discontinued on suspicion or evidence of these adverse reactions.

Idiopathic intracranial hypertension

Idiopathic intracranial hypertension (pseudotumor cerebri) has been reported in patients receiving mesalazine. Patients should be warned for signs and symptoms of idiopathic intracranial hypertension, including severe or recurrent headache, visual disturbances or tinnitus. If idiopathic intracranial hypertension occurs, discontinuation of mesalazine should be considered.

Cases of nephrolithiasis have been reported with the use of mesalazine including stones with a 100% mesalazine content. It is recommended to ensure adequate fluid intake during treatment.

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.

Mesalazine may produce red-brown urine discoloration after contact with sodium hypochlorite bleach (e.g. in toilets cleaned with sodium hypochlorite contained in certain bleaches).

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. Combination therapy with Pentasa and azathioprine or 6-mercaptopurine or thioguanine have shown a higher frequency of myelosuppressive effects, and an interaction cannot be ruled out, however, the mechanism behind the interaction is not established. Regular monitoring of white blood cells is recommended and the dosage regimen of thiopurine should be adjusted accordingly.

There is weak evidence that mesalazine might decrease the anticoagulant effect of warfarin.

4.6. Fertility, pregnancy and lactation

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. The underlying condition itself (Inflammatory bowel disease (IBD)) may increase risks for adverse pregnancy outcome.

Pregnancy: Mesalazine is known to cross the placental barrier and its concentration in umbilical cord plasma is lower than the concentration in maternal plasma. The metabolite acetyl-mesalazine is found at similar concentrations in umbilical cord and maternal plasma. Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/foetal development, parturition or postnatal development. There are no adequate and well controlled studies of Pentasa use in pregnant women. Limited published human data on mesalazine show no increase in the overall rate of congenital malformations. Some data show an increased rate of preterm birth, stillbirth, and low birth weight; however, these adverse pregnancy outcomes are also associated with active inflammatory bowel disease.

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

In one single case after long-term use of a high dose of mesalazine (2-4g, orally) during pregnancy, renal failure in a neonate was reported.

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. No controlled studies with Pentasa Sachet 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 cannot be excluded. 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

Pentasa Sachet has no or negligible influence on the ability to drive or use machines

4.8. Undesirable effects

Summary of the safety profile

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, and severe cutaneous adverse reactions (SCARs), including Drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens- Johnson syndrome (SJS) and Toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment (see section 4.4).

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

SOC

Common

≥1/100 to <1/10

Rare

≥1/10,000 to ≤1/1,000

Very rare

≤1/10,000

Not Known

(cannot be estimated from the available data).

Blood and the lymphatic system disorders

Altered blood counts (anaemia, aplastic anaemia, agranulocytosis, neutropenia, leukopenia (incl. granulocytopenia), pancytopenia, thrombocytopenia, and eosinophilia (as part of an allergic reaction).

Immune system disorders

Hypersensitivity reaction including anaphylactic reaction,

Nervous system disorders

Headache

Dizziness

Peripheral neuropathy

Idiopathic intracranial hypertension (see section 4.4)

Cardiac disorders

Myocarditis*

Pericarditis*

Pericardial effusion

Respiratory, thoracic and mediastinal disorders

Allergic alveolitis, allergic and fibrotic lung reactions (incl. dyspnoea, coughing, bronchospasm, pulmonary eosinophilia, interstitial lung disease, pulmonary infiltration, pneumonitis)

Gastrointestinal disorders

Diarrhoea

Abdominal pain

Nausea

Vomiting

Flatulence

Acute pancreatitis*

Increased amylase (blood and/or urine)

Pancolitis

Hepato-biliary disorders

Increased liver enzymes, cholestasis parameters and bilirubin, hepatotoxicity (incl. hepatitis*, cholestatic hepatitis, cirrhosis, hepatic failure)

Skin and subcutaneous tissue disorders

Rash (incl. urticaria, erythematous rash)

Photosensitivity**

(Reversible) alopecia

Quincke's oedema, dermatitis allergic,

Erythema multiforme

Stevens-Johnson Syndrome (SJS)/Toxic epidermal necrolysis (TEN) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Musculoskeletal and connective tissue disorders

Myalgia

Arthralgia

Lupus erythematosus-like reactions

Renal and urinary disorders

Renal function impairment

(incl. acute and chronic interstitial nephritis*, nephrotic syndrome, renal insufficiency)

Nephrolithiasis ***

Urine discolouration ***

Reproductive system and breast disorders

Oligospermia (reversible)

General disorders and administration site conditions

Drug Fever

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

(**) Photosensitivity: More severe reactions are reported in patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema.

(***) See section 4.4 for further information.

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

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, website: www.mhra.gov.uk/yellowcard.

4.9. Overdose

Acute 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 5 g/kg were not lethal.

Human experience: There is limited clinical experience with overdose of Pentasa sachet which does not indicate renal or hepatic toxicity. Since Pentasa is an amino salicylate, symptoms of salicylate toxicity may occur. Symptoms of salicylate over dosage are well described in the literature.

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

There is no specific antidote and treatment is symptomatic and supportive. The treatment at hospital includes close monitoring of renal function.