4.1. Therapeutic indications

Salcrozine is indicated for:

- Treatment of the acute phase of mild or moderate ulcerative colitis.

- Maintenance treatment of remission in ulcerative colitis.

4.2. Posology and method of administration

Posology

During the acute inflammatory phase and in long-term maintenance therapy, the patient must accurately follow the treatment established by the doctor to ensure the intended therapeutic effect.

Adults

The dosage should be adjusted according to patient response. The following dosage is recommended:

• Ulcerative colitis (acute phase): 1.5 - 4 g mesalazine daily, once daily or in divided doses. The dose of 4 g is recommended for patients who do not respond to lower doses of mesalazine. The effect of the treatment should be evaluated 8 weeks after initiation.

• Ulcerative colitis (maintenance): 1.5 – 3 g mesalazine daily, once daily or in divided doses. The dose of 3 g is recommended for patients who do not respond to lower doses of mesalazine and for those who required higher doses during acute phase.

Elderly

No studies have been carried out. Administration of Salcrozine in the elderly must be performed with caution and always limited to patients with normal renal function.

Paediatric population

The safety and efficacy of mesalazine in children and adolescents aged younger than 18 years of age has not been established. Do not administer to children under 5 years.

Method of administration

Oral use.

The tablets must be administered before meals and must be taken whole with some fluid.

Salcrozine gastro-resistant tablets consist of a mesalazine-containing core and an inert coating. Modified release of mesalazine is dependent on an intact coating. For this reason, the tablets should not be divided, chewed or crushed.

4.3. Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

- Pre-existing hypersensitivity to salicylic acid and its derivatives

- Severe impairment of hepatic and renal function

- Haemorrhagic diathesis

4.4. Special warnings and precautions for use

• Patients with severe liver or renal insufficiency. As mesalazine, also known as 5-aminosalicylic acid (5-ASA), is eliminated mainly by acetylation and subsequent urinary excretion, patients with impaired liver function or renal failure should be closely monitored, so it is advisable to perform liver and renal function tests before instituting treatment and regularly during it. Treatment with Salcrozine should be stopped immediately if there is evidence of renal deterioration. In patients who develop renal impairment during treatment, mesalazine-induced nephrotoxicity should be suspected.

• 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.

• There have been reports of increases in liver enzyme levels in patients taking preparations with mesalazine. Liver function should be evaluated before and during treatment according to medical criteria. Caution is advised if Salcrozine is given to patients with hepatic impairment. (see 4.3 Contraindications).

• Patients with a history of hypersensitivity to sulfasalazine should be kept under close medical surveillance. In case of acute intolerance reactions, such as abdominal cramps, acute abdominal pain, fever, severe headache and rashes, treatment should be discontinued immediately.

• Patients with pulmonary diseases, particularly asthma, should be carefully monitored during treatment.

• Cardiac hypersensitivity reactions induced by mesalazine (myo- and pericarditis) have been rarely reported. Caution should be exercised when treating patients, with conditions that predispose them to myocarditis or pericarditis, with mesalazine. If there is a suspicion of a cardiac hypersensitivity reaction, products containing mesalazine should not be re-administered.

• In rare occasions, serious blood dyscrasias have been reported after treatment with mesalazine. Haematological investigations should be performed if patients suffer unexplained haemorrhages, bruises, purpura, anaemia, fever or pharyngolaryngeal pain. Treatment with Salcrozine should be discontinued in case of suspected blood dyscrasia (see sections 4.3 and 4.5).

• Caution is recommended when treating patients with active gastric or duodenal ulcer.

• Salcrozine gastro-resistant tablets should not be administered concomitantly with lactulose-type laxatives or the like, since it lowers the pH of the faeces and may prevent the release of the active ingredient.

• Blood tests (differential blood count; liver function tests such as ALT and serum creatinine) should be determined prior to and during treatment, at the discretion of the treating physician.

• 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.

Mesalazine should be discontinued, at the first appearance of signs and symptoms of severe skin reactions, such as skin rash, mucosal lesions, or any other sign of hypersensitivity.

• 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).

• 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.

This medicinal product contains 49 mg sodium per gastro-resistant tablet, equivalent to 2.5 % of the WHO recommended maximum daily dietary intake of 2 g sodium for an adult.

The maximum daily dose of this product is equivalent to 20 % of the WHO recommended maximum daily intake for sodium.

Salcrozine is considered high in sodium. This should be particularly taken into account for those on a low salt diet.

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

In common with other salicylates, mesalazine can:

• Reduce the anticoagulant activity of anticoagulants derived from coumarin, such as warfarin.

• Enhance the glucose-lowering effects of sulfonylureas.

• Antagonize the uricosuric effects of probenecid and sulfinpyrazone.

• Express the toxicity of salicylates at lower doses than usual when administered with furosemide due to competition for renal excretion sites.

• Increase the risk of adverse renal reactions with the concomitant use of known nephrotoxic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs) and azathioprine.

• Increase the myelosuppressive effects of azathioprine, 6-mercaptopurine or thioguanine. Caution is advised in patients treated with azathioprine, 6-mercaptopurine or thioguanine and mesalazine since it may increase the possibility of blood dyscrasias. The haematological parameters (especially leucocytes and thrombocytes) should be monitored regularly, especially at the beginning of such a therapeutic combination.

• Decrease the natriuretic effect of spironolactone.

• Mesalazine may delay the excretion of methotrexate.

• Lactulose-type laxatives or similar can prevent the release of mesalazine from the gastro-resistant tablet, which would reduce its effect (see section 4.4 Special warnings and special precautions for use).

4.6. Fertility, pregnancy and lactation

Mesalazine 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 the 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 mesalazine 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 (leukopenia, thrombocytopenia, anaemia) have been reported in new-borns of mothers being treated with mesalazine.

In one single case after long-term use of a high dose of mesalazine (2 – 4 g, 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 mesalazine during breast-feeding have been carried out. There is limited data available on the use of oral mesalazine in breast-feeding women.

Hypersensitivity reactions like diarrhoea cannot be excluded. If the infant develops diarrhoea, breast-feeding should be discontinued.

Fertility

Studies in animals have shown no effects of mesalazine on male and female fertility (see section 5.3). There are no or limited data on the effect of mesalazine on fertility in humans.

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Salcrozine 500 mg gastro-resistant tablets is considered to have negligible influence on these abilities.

4.8. Undesirable effects

Adverse reactions are listed in the table below by system organ class and frequency. Frequencies are defined as: 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).

Organ Class System

Frequency According to MedDRA Convention

Rare (≥ 1/10 000 to < 1/1 000)

Very rare (< 1/10 000)

Not Known (Cannot be estimated from the available data)

Blood and lymphatic system disorders

Altered blood counts (agranulocytosis, pancytopenia, leukopenia, neutropenia, thrombocytopenia, aplastic anaemia)

Immune system disorders

Hypersensitivity reactions such as allergic exanthema, drug fever, lupus erythematosus syndrome, pancolitis.

Nervous system disorders

Headache, dizziness

Peripheral neuropathy

Idiopathic intracranial hypertension (see section 4.4)

Cardiac disorders

Myocarditis, pericarditis.

Respiratory, thoracic and mediastinal disorders

Allergic lung reactions (dyspnoea, cough, allergic alveolitis, eosinophilic pneumonia, lung infiltration, pneumonitis).

Gastrointestinal disorders

Discomfort, nausea, abdominal pain, diarrhoea, flatulence, vomiting.

Acute pancreatitis.

Worsening of colitis symptoms

Hepatobiliary disorders

Changes in liver function parameters (increase in transaminases and cholestasis parameters), hepatitis, cholestatic hepatitis.

Skin and subcutaneous tissue disorders

Photosensitivity*

Alopecia, erythema multiforme.

Drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)**

Musculoskeletal and connective tissue disorders

Myalgia, arthralgia.

Renal and urinary disorders

Interstitial nephritis, renal insufficiency, nephrotic syndrome.

Nephrolithiasis

Reproductive system and breast disorders

Oligospermia (reversible).

* PhotosensitivityMore severe reactions have been reported in patients with pre-existing skin conditions, such as atopic dermatitis and atopic eczema.

** 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).

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Mesalazine is an aminosalicylate, and signs of salicylate toxicity include tinnitus, vertigo, headache, confusion, drowsiness, pulmonary oedema, dehydration as a result of sweating, diarrhoea and vomiting, hypoglycaemia, hyperventilation, disruption of electrolyte balance and blood-pH and hyperthermia.

There is no specific antidote for mesalazine overdose and treatment is symptomatic and supportive. Conventional therapy for salicylate toxicity may be beneficial in the event of acute overdosage. Hypoglycaemia, fluid and electrolyte imbalance should be corrected by the administration of appropriate therapy. Adequate renal function should be maintained.