- For the treatment of acute episodes and the maintenance of remission of ulcerative colitis.

Posology

Adults and elderly

Depending upon the clinical requirements in individual cases, the following daily doses are recommended:

For the treatment of acute episodes: 1.5g to 3.0g mesalazine in three divided doses (1 or 2 tablets of Salofalk 500mg three times daily).

For the maintenance of remission: 1.5g mesalazine in three divided doses (1 tablet of Salofalk 500mg three times daily).

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. The total dose should not exceed the maximum adult dose.

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

It is generally recommended that half the adult dose may be given to children up to a body weight of 40kg; and the normal adult dose to those above 40kg.

Duration of treatment

The treatment of acute episodes of ulcerative colitis usually lasts 8 weeks. The duration of use is determined by the physician.

For maintenance of remission in ulcerative colitis, the dose can usually be reduced to 1.5g mesalazine/day (adults and adolescents with a body weight over 40kg) and 0.75g mesalazine/day (children/adolescents).

Method of administration:

Salofalk 500mg tablets should be taken in the morning, at midday and in the evening, 1 hour before meals. They should be swallowed whole, not chewed, and taken with plenty of fluid.

Treatment with Salofalk 500mg tablets should be administered regularly and consistently, both in the acute inflammatory stage and during maintenance therapy in order to achieve the desired therapeutic effect.

Salofalk 500mg tablets are contraindicated in cases of

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

- Severe impairment of hepatic or renal function.

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.

Caution is recommended in patients with impaired hepatic function.

Mesalazine should not be used in patients with impaired renal function. Mesalazine-induced renal toxicity should be considered if renal function deteriorates during treatment. If this is the case, Salofalk 500mg tablets should be discontinued immediately.

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).

Serious blood dyscrasias have been reported very rarely with mesalazine. Hematological investigations should be performed if patients suffer from unexplained haemorrhages, bruises, purpura, anaemia, fever or pharyngolaryngeal pain. Salofalk 500mg tablets should be discontinued in case of suspected or confirmed blood dyscrasia.

Cardiac hypersensitivity reactions (myocarditis, and pericarditis) induced by mesalazine have been rarely reported. Salofalk 500mg tablets should then be discontinued immediately.

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

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.

Patients with a history of adverse drug reactions to preparations containing sulphasalazine should be kept under close medical surveillance on commencement of a course of treatment with mesalazine. Should Salofalk 500mg tablets cause acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, severe headache and rash, therapy should be discontinued immediately.

Note

In rare cases, in patients who have undergone bowel resection/bowel surgery in the ileocoecal region with removal of the ileocoecal valve, it has been observed that Salofalk 500mg tablets were excreted undissolved in the stool, due to an excessively rapid intestinal passage.

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

Specific interaction studies have not been performed.

In patients who are concomitantly treated with azathioprine, 6-mercaptopurine or thioguanine, a possible increase in the myelosuppressive effects of azathioprine, 6-mercaptopurine or thioguanine should be taken into account.

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

Pregnancy

There are no adequate data on the use of mesalazine in pregnant women. However, 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.

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.

Animal studies on oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/fetal development, parturition or postnatal development.

Salofalk 500mg tablets should only be used during pregnancy if the potential benefit outweighs the possible risk.

Breast-feeding

N-acetyl-5-aminosalicylic acid and to a lesser degree mesalazine are excreted in breast milk. Only limited experience during lactation in women is available to date. Hypersensitivity reactions such as diarrhoea in the infant cannot be excluded. Therefore, Salofalk 500mg tablets 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.

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

* see section 4.4 for further information

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).

Photosensitivity

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

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

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.

Pharmacotherapeutic group: Intestinal anti-inflammatory agents, Aminosalicylic acid and similar agents

ATC code: A07EC02

Mechanism of action

The mechanism of the anti-inflammatory action is unknown. The results of in vitro studies indicate that inhibition of lipoxygenase may play a role.

Effects on prostaglandin concentrations in the intestinal mucosa have also been demonstrated. Mesalazine (5-Aminosalicylic acid / 5-ASA) may also function as a radical scavenger of reactive oxygen compounds.

Pharmacodynamic effects

Mesalazine, orally administered, acts predominantly locally at the gut mucosa and in the submucous tissue from the luminal side of the intestine. It is important, therefore, that mesalazine is available at the regions of inflammation. Systemic bioavailability / plasma concentrations of mesalazine therefore are of no relevance for therapeutic efficacy, but rather a factor for safety. In order to fulfil these criteria, Salofalk 500mg tablets are coated with Eudragit L; they are thus gastro-resistant and release of mesalazine is pH-dependent.

General considerations of mesalazine

Absorption

Mesalazine absorption is highest in proximal gut regions and lowest in distal gut areas.

Biotransformation

Mesalazine is metabolised both pre-systemically by the intestinal mucosa and the liver to the pharmacologically inactive N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). The acetylation seems to be independent of the acetylator phenotype of the patient. Some acetylation also occurs through the action of colonic bacteria. Protein binding of mesalazine and N-Ac-5-ASA is 43% and 78%, respectively.

Elimination

Mesalazine and its metabolite N-Ac-5-ASA are eliminated via the faeces (major part), renally (varies between 20 and 50 %, dependent on kind of application, pharmaceutical preparation and route of mesalazine release, respectively), and biliary (minor part). Renal excretion predominantly occurs as N-Ac-5-ASA.

About 1 % of total orally administered mesalazine dose is excreted into the breast milk mainly as N-Ac-5-ASA.

Salofalk 500mg tablets specific

Distribution

A combined pharmacoscintigraphic/pharmacokinetic study showed that Salofalk 500mg tablets, reach the ileocoecal region after approximately 3-4 hours in fasting subjects and reach the ascending colon within approximately 4– 5 hours. The total transit time in the colon is approximately 17 hours.

Absorption

Release of mesalazine from Salofalk 500mg tablets, begins after a lag-phase of approximately 3– 4 hours. Peak plasma concentrations are reached after approximately 5 hours (ileocoecal region) and, at 3 x 500 mg mesalazine/ day under steady-state conditions, are 3.0 ± 1.6 µ g/ml for mesalazine and 3.4 ± 1.6 µ g/ml for the metabolite, N-Ac-5-ASA.

Elimination

The total renal elimination rate for mesalazine and N-Ac-5-ASA over 24 hours during multiple intake (3 x 1 Salofalk 500mg tablets, for 2 days; 1 tablet on the third day=examination day) was approximately 60%. The non-metabolised mesalazine fraction after oral administration was approximately 10%.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenicity (rat) or toxicity to reproduction.

Kidney toxicity (renal papillary necrosis and epithelial damage in the proximal convoluted tubule or the whole nephron) has been seen in repeat-dose toxicity studies with high oral doses of mesalazine. The clinical relevance of this finding is unknown.

Basic butylated methylacrylate copolymer (Ph.Eur.) (=Eudragit E)

Calcium stearate (Ph.Eur.)

Cellulose, microcrystalline

Croscarmellose sodium

Glycine

Hypromellose

Macrogol 6000

Methacrylic acid-methyl methacrylate copolymer (1:1) (Ph.Eur.) (=Eudragit L)

Povidone K25

Silica, colloidal anhydrous

Sodium carbonate

Talc

Colouring agents: titanium dioxide (E 171), iron oxide hydrate (E 172)

Not applicable.

3 years.

Do not store above 25° C.

Blister: PVC/PVDC (orange-transparent) /aluminium blister foil

Package sizes: 20, 45, 50, 90, 100 and 300 Salofalk 500mg tablets

Not all package sizes will be marketed.

No special requirements.