SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Salofalk 500mg gastro-resistant tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet of Salofalk 500mg gastro-resistant tablets contains 500 mg mesalazine. Excipients: sodium carbonate and croscarmellose sodium For a full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Gastro-resistant tablets

Appearance: oval, light yellow to ochre, gastro-resistant tablets, matt with smooth surface; not scored.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

Posology and method of administration

Adults and elderly

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

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

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

Children:

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 40 kg; and the normal adult dose to those above 40 kg.

General instructions for use:

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.

The duration of use is determined by the physician.

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

4.3 Contraindications

Salofalk 500mg tablets are contraindicated in cases of:

•    Known hypersensitivity to salicylates or any of the excipients

•    Severe impairment of hepatic or renal function.

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 500mg 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 500mg 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 500mg tablets. 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.

1 Salofalk 500mg tablet contains 2.1 mmol (49mg) 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

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.

4.6    Fertility, pregnancy and lactation

Pregnancy

There are no adequate data on the use of Salofalk 500mg tablets 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 500mg 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. Hypersensitivity reactions such as diarrhoea in the infant cannot be excluded. Therefore, Salofalk 500mg tablets should only be used during breastfeeding 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

No effects on the ability to drive and use machines have been observed

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 erythematosus syndrome, pancolitis
Hepatobiliary disorders		Changes in liver function parameters (increase in transaminases and parameters of cholestasis), hepatitis, cholestatic hepatitis
Reproductive system disorders		Oligospermia (reversible)

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 500mg tablets are coated with Eudragit L; they are thus gastro-resistant and release of mesalazine is pH-dependent.

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 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 pg/ml for mesalazine and 3.4 ± 1.6 pg/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%.

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

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, anhydrous Talc

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

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

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.

6.6    Special precautions    for    disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Dr. Falk Pharma GmbH Leinenweberstr. 5 79108 Freiburg Germany

Tel: +49 (0)761 1514-0

8    MARKETING AUTHORISATION NUMBER(S)

PL 08637/0019

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/06/2009

10 DATE OF REVISION OF THE TEXT

02/01/2012