SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Salofalk 500mg gastro-resistant prolonged-release granules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each sachet of Salofalk 500mg granules contains 500mg mesalazine.

Excipients with known effect:

Each sachet of Salofalk 500mg granules contains 1.0mg aspartame and 0.02mg sucrose. For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Gastro-resistant prolonged-release granules.

Description: Stick-formed or round, greyish white granules

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

4.2    Posology and method of administration

Posology Adults and elderly

For the treatment of acute episodes of ulcerative colitis:

Once daily 1 sachet of Salofalk 3g granules, 1 or 2 sachets of Salofalk 1.5g granules, 3 sachets of Salofalk 1000mg granules or 3 sachets of Salofalk 500mg granules (equivalent to 1.5 - 3.0g mesalazine daily) preferably to be taken in the morning according to the individual clinical requirement.

It is also possible to take the prescribed daily dose in three divided doses (1 sachet of Salofalk 500mg granules three times daily or 1 sachet of Salofalk 1000mg granules three times daily) if this is more convenient to the patient.

For the maintenance of remission of ulcerative colitis:

The standard treatment is 0.5 g mesalazine three times daily (in the morning, at midday and in the evening) corresponding to a total dose of 1.5g mesalazine per day. For patients known to be at increased risk for relapse for medical reasons or due to difficulties to adhere to application of three daily doses the dosing schedule can be adapted to 3.0g mesalazine given as a single daily dose preferably in the morning.

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 30-50mg/kg/day once daily preferably in the morning or in divided doses. Maximum dose: 75mg/kg/day. The total dose should not exceed the maximum adult dose.

Maintenance treatment: To be determined individually, starting with 15-30mg/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.

Method of administration

The contents of the sachets of Salofalk granules should not be chewed. The granules should be taken on the tongue and swallowed, without chewing, with plenty of liquid.

Both in the treatment of acute inflammatory episodes and during long term treatment, Salofalk granules should be used on a regular basis and consistently in order to achieve the desired therapeutic effects.

The duration of use is determined by the physician.

4.3 Contraindications

Salofalk granules are contra-indicated in cases of:

•    hypersensitivity to the active substance, to salicylates or 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 granules 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 granules.

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 granules. Should Salofalk granules cause acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, severe headache and rash, therapy should be discontinued immediately.

In patients with phenylketonuria it should be kept in mind that Salofalk 500mg granules contain aspartame as a sweetening agent, equivalent to 0.56mg phenylalanine.

Salofalk granules contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Specific interaction studies have not been performed.

Lactulose or similar preparations, which lower stool pH:

• possible reduction of mesalazine release from granules due to decreased pH caused by bacterial metabolism of lactulose.

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.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data on the use of Salofalk granules in pregnant women. However, data on a limited number of exposed pregnancies indicate no adverse effect of mesalazine on pregnancy or on the health of 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 (2-4g, 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/foetal development, parturition or postnatal development.

Salofalk granules 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. Hypersensitivity reactions such as diarrhoea in the infant cannot be excluded. Therefore, Salofalk granules should only be used during breast-feeding if the potential benefit outweighs the possible risk. If the infant develops diarrhoea, breastfeeding should be discontinued.

4.7    Effects on ability to drive and use machines

Salofalk granules have no or negligible influence on the ability to drive or use machines.

4.8    Undesirable effects

Organ Class System	Frequency According to MedDRA Convention
	rare (>1/10,000 to 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 erythematosus syndrome, pancolitis
Hepatobiliary disorders		Changes in liver function parameters (increase in

		transaminases and parameters of cholestasis), hepatitis, cholestatic hepatitis
Reproductive system and breast disorders		Oligospermia (reversible)

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 at: 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 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 realise this, Salofalk granules are gastric juice resistant and release mesalazine in a pH dependent manner due to an Eudragit L coating, and prolonged manner due to the matrix granule structure.

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

Salofalk Granules specific:

Distribution:

Owing to the granule size of about 1 mm, transit from the stomach to the small intestine is fast.

A combined pharmacoscintigraphic/pharmacokinetic study showed that the compound reaches the ileocaecal region within approx. 3 hours and the ascending colon within approx. 4 hours. The total transit time in the colon amounts to about 20 hours. Approximately 80 % of an administered oral dose is estimated to be available in the colon, sigmoid and rectum.

Absorption:

Mesalazine release from Salofalk granules starts after a lag phase of about 2-3 hours, peak plasma concentrations are reached at about 4-5 hours. The systemic bioavailability of mesalazine after oral administration is estimated to be approximately 15-25 %.

Food intake delays absorption for 1 to 2 hours but does not change the rate and extent of absorption.

Elimination:

From a 3 x 500 mg daily mesalazine dose, a total renal elimination of mesalazine and N-Ac-5-ASA under steady state condition was calculated to be about 25 %. The unmetabolised excreted mesalazine part was less than 1 % of the oral dose. The elimination half-life in this study was 4.4 hours.

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

Aspartame (E 951)

Carmellose sodium Cellulose, microcrystalline Citric acid, anhydrous Hypromellose Magnesium stearate

Methacrylic acid-methyl methacrylate copolymer (1:1) (Eudragit L 100) Methylcellulose

Polyacrylate dispersion 40 % (Eudragit NE 40 D containing 2 % Nonoxynol 100)

Povidone K 25

Silica, colloidal anhydrous

Simeticone

Sorbic acid

Talc

Titanium dioxide (E 171)

Triethyl citrate

Vanilla custard flavouring (containing sucrose)

6.2    Incompatibilities

Not applicable.

6.3    Shelf-Life

4 years.

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5    Nature and contents    of container

Sachet of polyester/aluminium/polyethylene-foil.

Each sachet of Salofalk 500mg granules contains 0.93 g granules.

Package sizes: 50 sachets, 100 sachets and 300 sachets Salofalk 500mg granules

Not all package sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Dr. Falk Pharma GmbH Leinenweberstr. 5 P. O. Box 6529 79041 Freiburg Germany

Tel: +49 (0)761 1514-0

8    MARKETING AUTHORISATION NUMBER(S)

PL 08637 / 0007

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

10 DATE OF REVISION OF THE TEXT

13/06/2014