Salofalk 1000mg gastro-resistant prolonged release granules

Each sachet of Salofalk 1000mg granules contains 1000 mg mesalazine.

Excipient:

Each sachet of Salofalk 1000mg granules contains 2.0 mg aspartame.

For a full list of excipients, see section 6.1.

Gastro-resistant prolonged release granules.

Description: Stick-formed or round, greyish white granules.

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

Adults and elderly:

For the treatment of acute episodes of ulcerative colitis:

Once daily 3 sachets of Salofalk 500mg granules or 3 sachets of Salofalk 1000mg granules (equivalent to 1.5 – 3.0 g mesalazine daily) preferably to be taken in the morning according to the individual clinical necessities.

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:

1 sachet of Salofalk 500mg granules three times daily (equivalent to 1.5 g mesalazine daily).

Children below 6 years of age:

Salofalk granules should not be used in children under 6 years of age because there is very limited experience with this age group.

Children older than 6 years of age and adolescents:

In acute attacks, depending on disease severity, 30-50 mg mesalazine/kg/day should be given once daily preferably in the morning or in 3 divided doses. For maintenance of remission, 15-30 mg mesalazine/kg/day may be given in 2 divided doses. 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.

All patients:

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.

In general, an acute episode of ulcerative colitis subsides after 8-12 weeks; the dosage can then, in most patients, be reduced to the maintenance dose.

Salofalk granules are contra-indicated in cases of:

• Pre-existing hypersensitivity to salicylic acid and its derivatives or to any of the other constituents.

• Severe impairment of hepatic and renal function.

• Pre-existing gastric or duodenal ulcer.

• Haemorrhagic diathesis.

Blood tests (differential blood count; liver function parameters like 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, controls are recommended 14 days after commencement of treatment, then a further two to three times at intervals of 4 weeks.

If the findings are normal, control examinations should be carried out every 3 months. If additional symptoms occur, control examinations should be performed immediately.

Caution is recommended in patients with impaired hepatic function.

Salofalk granules are not recommended 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 sulfasalazine should be kept under close medical surveillance on commencement of a course of treatment with Salofalk granules. Should Salofalk granules cause acute intolerability reactions such as 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 1000mg granules contain aspartame as a sweetening agent, equivalent to 1.12 mg phenylalanine.

Salofalk granules should not be used for the treatment of children below the age of 6 years.

Specific interaction studies have not been performed.

Interactions may occur during treatment with Salofalk granules and concomitant administration of the following medicinal products. Most of these possible interactions are based on theoretical reasons:

- Coumarin-type anticoagulants:

possible potentiation of the anticoagulant effects (increasing the risk of gastrointestinal haemorrhage)

- Glucocorticoids:

possible increase in undesirable gastric effects

- Sulphonylureas:

possible increase in the blood glucose-lowering effects

- Methotrexate:

possible increase in the toxic potential of methotrexate

- Probenecid/sulphinpyrazone:

possible attenuation of the uricosuric effects

- Spironolactone/frusemide:

possible attenuation of the diuretic effects

- Rifampicin:

possible attenuation of the tuberculostatic effects

- Lactulose or similar preparations, which lower stool pH:

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

In patients who are concomitantly treated with azathioprine or 6-mercaptopurine, possible enhanced myelosuppressive effects of azathioprine or 6-mercaptopurine should be taken into account.

There are no adequate data from the use of Salofalk granules in pregnant woman. 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 epidmiologic data are available. In one single case after long-term use of a high dose 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, embryonal / foetal development, parturition or postnatal development.

Salofalk granules should only be used during pregnancy if the potential benefit outweighs the possible risk.

N-acetyl-5-aminosalicylic acid and to a lesser degree mesalazine are excreted in breast milk. Only limited experience during lactation in woman is available to date. Hypersensivity reactions like diarrhoea can not be excluded. Therefore, Salofalk granules should only be used during breast-feeding if the potential benefit outweighs the possible risk. If the suckling neonate develops diarrhoea, the breast-feeding should be discontinued.

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

Gastrointestinal undesirable effects (rare, 0.01 % - < 0.1 %):

Abdominal pain, diarrhoea, flatulence, nausea, vomiting

Nervous system disorders:

Headache, dizziness (rare, 0.01 % - < 0.1 %)

peripheral neuropathy (very rare, < 0.01 %)

Renal undesirable effects (very rare, < 0.01 % ):

Impairment of renal function including acute and chronic interstitial nephritis and renal insufficiency

Hypersensitivity reactions (very rare, < 0.01 %):

Allergic exanthema, drug fever, bronchospasm, peri- and myocarditis, acute pancreatitis, allergic alveolitis, lupus erythematosus syndrome, pancolitis

Musculoskeletal disorders (very rare, < 0.01 %):

Myalgia, arthralgia

Blood and the lymphatic system disorders (very rare, < 0.01 %):

Altered blood counts (aplastic anaemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia)

Hepato-biliary disorders (very rare, < 0.01 %):

Changes in hepatic function parameters (increase in transaminases and parameters of cholestasis), hepatitis, cholestatic hepatitis

Skin and appendages disorders (very rare, < 0.01 %):

Alopecia

Reproductive system disorders (very rare, < 0.01 %):

Oligospermia (reversible)

No cases of intoxication have been reported to date and no specific antidotes are known.

If necessary, intravenous infusion of electrolytes (forced diuresis) should be considered in cases of overdose.

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 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.

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 un-metabolised excreted mesalazine part was less than 1 % of the oral dose. The elimination half-life in this study was 4.4 hours.

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.

Aspartame (E 951)

Carmellose sodium

Cellulose, microcrystalline

Citric acid, anhydrous

Silica, colloidal anhydrous

Hypromellose

Magnesium stearate

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

Methylcellulose

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

Povidone K 25

Simeticone

Sorbic acid

Talc

Titanium dioxide (E 171)

Triethyl citrate

Vanilla custard flavouring (containing propylene glycol)

Not applicable.

4 years.

No special precautions for storage.

Container: Polyester/ Aluminium/ Polyethylene-Foil

Package sizes: 20 sachets, 50 sachets, 60 sachets, 100 sachets or 150 sachets Salofalk 1000mg granules

Not all package sizes may be marketed.

No special requirements.

Dr. Falk Pharma GmbH

Leinenweberstr. 5

P. O. Box 6529

79041 Freiburg

Germany

Tel: +49 (0)761 1514-0

PL 08637/0008

Date of first authorisation: 15 October 2001

Date of renewal: 01 March 2007

February 2008