SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Salofalk® 250mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 250mg mesalazine.

Excipients: Sodium carbonate

For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Gastro-resistant tablet

Appearance: Round, butter-yellow to ochre, gastro-resistant tablets, matt with smooth surface; they are not scored.

4.    CLINICAL PARTICULARS

4.1.    Therapeutic indications

Treatment of mild to moderate acute exacerbations of ulcerative colitis and for the maintenance of remission of ulcerative colitis.

4.2 Posology and method of administration

Posology

Adults and elderly:

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

For treatment of acute episodes: 1.5g to 3.0g mesalazine daily in three divided doses (six to 12 tablets daily in three divided doses).

For the maintenance of remission: 1.5g mesalazine in three divided doses (six tablets daily in three divided doses - two 250mg tablets three times a day).

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: 75mg/kg/day in divided doses. The total dose should not exceed the maximum dose for adults.

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

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.

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) or 0.75g mesalazine/day (children/adolescents).

Method of Administration: Oral

General instructions for use:

Salofalk 250mg 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 250mg 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.

The duration of use is determined by the physician.

4.3 Contraindications

Salofalk 250mg 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.

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.

Caution is recommended in patients with impaired hepatic function.

Salofalk 250mg tablets should not be used in patients with impaired renal function. Mesalazine-induced renal toxicity should be considered if renal function deteriorates during treatment.

Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment with Salofalk 250mg tablets.

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 Salofalk 250mg tablets. Should Salofalk 250mg 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 250mg tablets were excreted undissolved in the stool, due to an excessively rapid intestinal passage. 1 Salofalk 250 mg tablet contains 48 mg sodium. This must be taken into consideration in patients on a sodium-controlled (low- sodium/low-salt) diet.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

In patients who are concomitantly treated with azathioprine, 6-mercaptopurine or or thioguaninea 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of Salofalk 250mg tablets 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 foetus/newborn child. To date no other relevant epidmiologic data are available. In one single case after long-term use of a high dose mesalazine (24g, 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.

Salofalk 250mg tablets 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. Only limited experience during lactation in women is available to date. Hypersensivity reactions such as diarrhoea in the infant cannot be excluded. Therefore, Salofalk 250mg 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.

4.7 Effects on ability to drive and use machines

Salofalk 250mg tablets have no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Organ Class System	Frequency According to MedDRA convention
	Rare (>1/10,000; <1/1,000)	Very rare (<1/10,000)
Blood and lymphatic system disorders		Altered blood counts (aplastic anaemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia)
Nervous system disorders	Headache, dizziness	peripheral neuropathy
Cardiac disorders	Myocarditis, Pericarditis
Respiratory, thoracic and mediastinal disorders		Allergic and fibrotic lung reactions (including dyspnoea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, lung infiltration, pneumonitis)
Gastrointestinal disorders	Abdominal pain, diarrhoea, flatulence, nausea, vomiting	Acute pancreatitis
Renal and urinary disorders		Impairment of renal function including acute and chronic interstitial nephritis and renal insufficiency
Skin and subcutaneous tissue disorders		Alopecia
Musculoskeletal and connective tissue disorders		Myalgia, arthralgia
Immune system disorders		Hypersensitivity reactions such as allergic exanthema, drug fever, lupus

Reporting of suspected 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:

Yellow Card Scheme

Website: www.mhra.gov .uk/yellowcard

4.9    Overdose

There are rare data on overdosage (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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Intestinal anti-inflammatory agent ATC code: A07EC02

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.

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 250mg tablets are coated with Eudragit L; they are thus gastro-resistant and release of mesalazine is pH-dependent.

Pharmacokinetic properties

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 breast milk mainly as N-Ac-5-ASA.

Salofalk 250mg tablet specific:

Distribution

A combined pharmacoscintigraphic/pharmacokinetic study in patients showed that Salofalk 250mg, gastro-resistant tablets, dissolve after approximately 3-4 hours in the ileum if they are taken concurrently with food (test meal). The median gastric emptying time was approximately 3 hours. After approximately 7 hours, the tablets reached the colon.

In a further study in volunteers, the duodeno-ileal transit time was approximately 3 hours, peak luminal 5-ASA concentrations being measured in the ileum 7-8 hours after concurrent administration of the tablets with the test meal. Approximately 75% of the mesalazine dose reached the colon in non-metabolised form.

Absorption

Release of mesalazine from Salofalk 250mg, gastro-resistant tablets, begins after a lag-phase of approximately 3-4 hours. Peak plasma concentrations are reached after approximately 5 hours (ileocoecal region) and, with 3 x 500 mg mesalazine/ day (3 x 2 Salofalk 250mg) under steady-state conditions, are 2.1 ± 1.7 pg/ml for mesalazine and 2.8 ± 1.7 pg/ml for the metabolite, N-Ac-5-ASA.

Elimination

In long-term therapy with Salofalk 250mg and with a daily dose of 500 mg mesalazine 3 times daily (steady-state conditions), the total renal elimination rate of mesalazine and N-Ac-5-ASA was approximately 55% (24-hour value after administration of last dose). The non-metabolised mesalazine fraction was approximately 5%. The elimination half-life was 0.7-2.4 hours (mean 1.4 0.6 hours) at a dose of 500 mg mesalazine, 3 times daily

5.3    Preclinical safety data

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.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sodium carbonate

Glycine

Povidone

Microcrystalline cellulose (E460) Colloidal anhydrous silica Calcium stearate

Hydroxypropylmethylcellulose (E464) Methacrylic acid copolymer (Eudragit L) Talc

Titanium dioxide (E171)

Iron oxide (E172)

Polyethylene glycol Polymethacrylate (Eudragit E)

6.2    Incompatibilities

Not applicable

6.3    Shelf life

3 years

6.4    Special precautions for storage

No special precautions for storage

6.5    Nature and contents of container

Orange PVC/PVDC/AI blister strips packed in cartons containing 10, 100 or 300 tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements

7    MARKETING AUTHORISATION HOLDER

Dr Falk Pharma UK Ltd Bourne End Business Park Cores End Road Bourne End Buckinghamshire SL8 5AS

8.    MARKETING AUTHORISATION NUMBER

PL 10341/0004

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

13 September 1991

10 DATE OF REVISION OF THE TEXT

20/05/2015