4.1. Therapeutic indications

Octasa is indicated in adults, children and adolescents above 6 years for:

Ulcerative Colitis:

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

Crohn's ileo-colitis:

For the maintenance of remission.

4.2. Posology and method of administration

Posology

Adults

Mild acute disease: 2.4 g (three tablets) once daily or in divided doses, with concomitant corticosteroid therapy to be taken when clinically indicated.

Moderate acute disease: 2.4 g to 4.8 g (three to six tablets) a day in divided doses, with concomitant corticosteroid therapy where clinically indicated. 2.4 g may be taken once daily or in divided doses. Above 2.4 g should be taken in divided doses.

Maintenance therapy: 1.6 g to 2.4 g (two to three tablets) taken once daily or in divided doses.

The maximum adult dose should not exceed six tablets a day and not exceed 3 tablets taken together at any one time.

Elderly population

The normal adult dosage may be taken unless liver or renal function is severely impaired (see section 4.3 and 4.4). No studies have been carried out in the elderly population.

Paediatric population

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 in divided doses. Maximum dose: 75 mg/kg/day in divided doses. The total dose should not exceed 4 g/day.

• Maintenance treatment: To be determined individually, starting with 15-30 mg/kg/day in divided doses. The total dose should not exceed 2 g/day.

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.

The tablets must be swallowed whole preferably with some liquid before food intake. They must not be chewed, crushed or broken before swallowing. If one or more doses have been missed, the next dose is to be taken as usual.

4.3. Contraindications

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

- Known hypersensitivity to salicylates

- Severe liver impairment

- Severe renal impairment (GFR less than 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 and then every 4 weeks for the following 12 weeks. If the findings are normal, follow-up tests should be carried out every three months. If additional signs appear, these tests should be performed immediately.

Renal impairment

Caution should be exercised in patients with raised serum creatinine or proteinuria. The possibility of mesalazine-induced nephrotoxicity should be suspected in patients developing impairment of renal function during treatment. Patients need to remain well hydrated whilst taking Octasa to reduce the risk of crystalluria and consequential kidney damage.

Treatment with Octasa should be stopped immediately if there is evidence of renal impairment and patients should seek immediate medical advice.

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.

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

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

Hepatic impairment

There have been reports of increased liver enzyme levels in patients taking preparations containing mesalazine. Caution is recommended if Octasa is administered to patients with liver impairment. Blood tests (liver function parameters such as ALT or AST) should be performed 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.

Cardiac hypersensitivity reactions

Mesalazine-induced cardiac hypersensitivity reactions (myo- and pericarditis) have rarely been reported with Octasa. In case of previous mesalazine-induced 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.

Adverse drug reactions 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

In case of existing gastric or duodenal ulcers treatment should begin with caution based on theoretical grounds.

Tablets in stool

A limited number of reports of intact tablets in the stool have been received. What appear to be intact tablets may in some cases represent largely empty shells of the coated tablets. If intact tablets are observed in the stool repeatedly, the patient should consult his/her physician.

Elderly population

Use in the elderly should be handled with caution and the product should only be prescribed to patients having a normal or non-severely impaired liver and renal function, see section 4.3.

Paediatric population

There is only limited documentation for an effect in children (age 6-18 years), see section 4.2.

Pharmaceutical excipients of special interest

Intolerance to carbohydrates

With reference to the presence of lactose monohydrate in the formulation, patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium content

This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, i.e. is essentially “sodium-free”.

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

No interaction studies have been performed.

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

In patients who are concomitantly treated with azathioprine, 6-mercaptopurine or thioguanine, a possible increase in the myelosuppressive effects of azathioprine, or 6-mercaptopurine or thioguanine should be taken into account. As a result, life-threatening infection can occur. Patients should be closely observed for signs of infection and myelosuppression. Haematological parameters, especially the leucocyte, thrombocyte, and lymphocyte cell counts should be monitored regularly (weekly), especially at initiation of such combination therapy, see section 4.4. If white blood cells are stable after 1 month, testing every 4 weeks for the following 12 weeks followed by 3 monthly monitoring intervals appears to be justified.

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 (627) 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.

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.

Breast-feeding

N-acetyl-mesalazine and, to a lesser degree, mesalazine are excreted in breast milk. The clinical significance of this has not been determined. Only limited experience in women during lactation is available to date. Hypersensitivity reactions like 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, the breast-feeding should be discontinued.

Fertility

No effects on fertility have been observed.

4.7. Effects on ability to drive and use machines

Octasa has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

a) Summary of the safety profile

Octasa 800 mg Modified Release Tablets have been evaluated in 140 patients with mild to moderate active ulcerative colitis in one controlled study lasting for 10 weeks comparing safety and efficacy versus another 141 patients receiving placebo. Treatment related undesirable effects in the Octasa group with the highest reporting rate were worsening of ulcerative colitis (3.6%), haematuria (2.9%), and ketonuria (2.1%). All undesirable effects with Octasa 800 mg Modified Release Tablets were of mild to moderate severity. Discontinuations due to adverse reactions occurred in 8.6% of patients in the Octasa group and in 21.3% of patients in the placebo group. Most of the drug related reactions that led to study drug discontinuation were related to worsening of ulcerative colitis.

Organ specific adverse drug reactions affecting the heart, lungs, liver, kidneys, pancreas, skin and subcutaneous tissue have been reported.

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

In addition to the undesirable effects reported above in a clinical trial with Octasa 800 mg Modified Release Tablets, undesirable effects relevant for the labeling reported from eight (8) double-blind and five (5) open clinical studies with 739 patients treated with Octasa 400 mg MR Tablets are listed below.

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)

Frequency not known

Blood and lymphatic system disorders

eosinophilia (as part of an allergic reaction)

altered blood counts (aplastic anemia, agranulocytosis, pancytopenia, neutropenia, leucopenia, thrombocytopenia)

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

Hepato-biliary 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, renal insufficiency, nephrotic syndrome and 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 with C-reactive protein increased and/or exacerbation of symptoms of underlying disease

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/mesalazine 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 myelosuppressive drugs, such as azathioprine, or 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 only limited safety experience with the use of Octasa 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 is an important way to gather more information to continuously monitor 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/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There are rare data on overdose (e.g. intended suicide with high oral doses of mesalazine), which do not indicate renal or hepatic toxicity. There is no specific antidote and treatment is symptomatic and supportive.