4.1. Therapeutic indications

Ulcerative colitis.

For the treatment of mild to moderate acute disease. For the maintenance of remission.

4.2. Posology and method of administration

Posology

Adults, including the elderly (>65 years)

The dose should be adjusted according to the severity of the disease and tolerance.

Acute disease: In the event of exacerbation, the dose can be increased to 4800 mg daily, once daily or in 2-3 divided doses.

Once clinical remission is achieved, the dose should gradually be decreased to maintenance dose.

Continued therapy should be carefully considered in subjects not responding by week 8.

Maintenance treatment: 1600 mg once daily.

Other oral mesalazine formulations are available if an alternative dose for maintenance treatment is considered more appropriate.

Elderly population

No studies have been carried out in older people.

Paediatric population

The safety and efficacy of Octasa in children and adolescents aged younger than 18 years of age has not been established.

Method of administration: oral.

The tablets must be swallowed whole with a glass of water. They must not be chewed, crushed or broken before swallowing. The tablets can be taken with or without food. If one or more doses have been missed, the next dose is to be taken as usual.

4.3. Contraindications

• Hypersensitivity to salicylates (including mesalazine) or any of the excipients listed in section 6.1.

• Severe liver impairment.

• Severe renal impairment (GFR < 30 ml/min/1.73 m2)

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 3 months. If additional symptoms occur, these tests should be performed immediately.

Renal impairment

Octasa should not be used in patients with renal impairment. Mesalazine-induced renal toxicity shall be suspected if the renal function is impaired during the treatment and the treatment should be stopped immediately.

It is recommended that the renal function is monitored prior to and repeatedly whilst on Octasa therapy.

Nephrolithiasis

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.

Urine Discoloration

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).

Severe cutaneous adverse reactions

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.

Blood dyscrasia

Very rarely have serious blood dyscrasia been reported. Octasa therapy should be stopped immediately if there is a suspicion or evidence of blood dyscrasia (signs of unexplained bleeding, bruising, purpura, anaemia, persistent fever or sore throat), and the patient should seek immediate medical advice.

Liver impairment

There have been reports of increased liver enzyme levels in patients taking preparations containing Octasa. Caution is recommended if Octasa is administered to patients with liver impairment.

Cardiac hypersensitivity reactions

Mesalazine-induced hypersensitivity reactions (myo- and pericarditis) have been reported rarely with Octasa. In case of a suspected cardiac hypersensitivity, Octasa must not be reintroduced. Caution should be taken in patients with previous myo- or pericarditis of allergic background regardless of its origin.

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.

Pulmonary disease

Patients with pulmonary disease, in particular asthma, should be very carefully monitored during treatment with Octasa.

Hypersensitivity to sulphasalazine

Patients with a history of adverse drug reactions to sulphasalazine, therapy should be kept under close medical supervision. Treatment must be stopped immediately if acute symptoms of intolerance occur such as abdominal cramps, acute abdominal pain, fever, severe headache and rash.

Gastric and duodenal ulcers

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

Asacol contains sodium

Each tablet contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

Elderly patients

Octasa should be administered with caution in elderly patients , it should only be given to patients with normal renal or hepatic function or mild to moderate renal or hepatic impairment (see section 4.3).

Paediatric population

There is only limited documentation for an effect in children, see section 4.2.

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

No interaction studies have been performed.

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

Caution is recommended for the concomitant use of mesalazine with known nephrotoxic agents, including non-steroidal anti-inflammatory drugs (NSAIDs) and azathioprine, or methothrexate as these may increase the risk of renal adverse reactions.

A possible increase in the myelosuppressive effects of azathioprine, 6-mercaptopurine or thioguanine in patients who are concomitantly treated with any of these preparations, should be taken into account. Life-threatening infection can occur. patients should be closely observed for signs of infection and myelosuppression. Haematological parameters, especially the leukocyte, thrombocyte and lymphocyte cell counts should be monitored regularly (weekly), especially at initiation of such combination therapy, see section 4.4.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data on the use of Octasa in pregnant women. However, data on a limited number of exposed pregnancies indicate no adverse effect of mesalazine on pregnancy or on the foetus/newborn child. To date, no other relevant epidemiologic data are available.

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.

Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development. Octasa should only be used during pregnancy if the potential benefit outweighs the possible risk.

Breastfeeding

N-acetyl-5-aminosalicylic acid and to a lesser degree mesalazine are excreted in breast milk. The clinical significance of this has not been determined. Only limited experience during lactation in women is available to date. Hypersensitivity reactions such as diarrhoea in the infant cannot be excluded. Therefore, Octasa 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

No effects on fertility have been observed.

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. Octasa is considered to have negligible influence on these abilities.

4.8. Undesirable effects

a) Summary of the safety profile

Organ specific adverse drug reactions affecting the heart, lungs, liver, kidneys, pancreas, skin and subcutaneous tissue have been reported. Headache (1.7%), haematuria (1.7%), abdominal pain (1.5%), ulcerative colitis (1.5%) and proteinuria (1.5%) are the most commonly reported drug related adverse events in the clinical development programme.

Treatment must be stopped immediately if acute symptoms of intolerance occur such as abdominal cramps, acute abdominal pain, fever, severe headache and rash.

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).

b) Tabulated summary of adverse reactions

Undesirable effects reported from clinical studies and other sources are listed below:

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), not known (cannot be estimated from the available data).

System Organ Class

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)

Not known

(Cannot be estimated from the available data)

Blood and Lymphatic System Disorders

Eosinophilia (as part of an allergic reaction).

Altered blood counts (aplastic anemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia), blood dyscrasia.

Immune System Disorders

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

Nervous System Disorders

Paresthesia

Headache, dizziness

Peripheral neuropathy

Idiopathic intracranial hypertension (see section 4.4)

Cardiac Disorders

Myocarditis, pericarditis

Respiratory, thoracic and mediastinal disorders

Allergic and fibrotic lung reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis), interstitial pneumonia, eosinophilic pneumonia, lung disorder.

Pleurisy

Gastrointestinal Disorders

Dyspepsia

Abdominal pain, diarrhoea, flatulence, nausea, vomiting

Acute pancreatitis

Hepatobiliary Disorders

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

Skin and Subcutaneous Tissue Disorders

Rash

Urticaria, pruritus

Photosensitivity*

Alopecia

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

Musculoskeletal, connective tissue and bone disorders

Myalgia, arthralgia

Lupus-like syndrome with pericarditis and pleuropericarditis as prominent symptoms as well as rash and arthralgia

Renal and Urinary Disorders

Impairment of renal function including acute and chronic interstitial nephritis and renal insufficiency, nephrotic syndrome, renal failure which may be reversible on early withdrawal.

Nephrolithiasis**

Reproductive system and breast disorders

Oligospermia (reversible)

General disorders and administration site conditions

Pyrexia, chest pain

Intolerance to mesalazine and/or exacerbation of disease, C-reactive protein increased

Investigations

Blood creatinine increased, weight decreased, creatinine clearance decreased, amylase increased, red blood cell sedimentation rate increased, lipase increased, BUN increased.

* see section c)

** See section 4.4 for further information

c) Description of selected adverse reactions

An unknown number of the above mentioned undesirable effects are probably associated to the underlying IBD rather than Octasa medication. This holds true especially for gastrointestinal undesirable effects, arthralgia, and alopecia.

To avoid blood dyscrasia resulting from developing bone marrow depression patients should be monitored with care, see section 4.4.

Under co-administration of mesalazine with immunosuppressive drugs such as azathioprine, 6-MP or thioguanine, life-threatening infection can occur, see section 4.5.

Photosensitivity

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

d) Paediatric population

There is no safety experience with the use of Octasa tablets in the paediatric population. It is expected that the target organs of possible adverse reactions in the paediatric population are the same as for adults (heart, lungs, liver, kidneys, pancreas, skin and subcutaneous tissue.

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.

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.