Salofalk 1g/actuation Rectal Foam.

1 actuation contains:

Mesalazine 1.0g

Excipients: cetostearyl alcohol, propylene glycol and meta bisulphite

For a full list of excipients, see section 6.1.

Rectal foam.

White-greyish to slightly reddish-violet, creamy firm foam.

Treatment of active, mild ulcerative colitis of the sigmoid colon and rectum.

Method of Administration: rectal.

Adults and adolescents above 12 years of age:

Two administrations once a day at bedtime. The canister is first fitted with an applicator and then shaken for about 20 seconds before the applicator is inserted into the rectum as far as comfortable. To administer a dose of Salofalk^®, the pump dome is fully pushed down and released. Note that the spray will only work properly when held with the pump dome pointing down. Following the first or second activation depending upon need (see below) the applicator should be held in position for 10-15 seconds before being withdrawn from the rectum. If the patient has difficulty in holding this amount of foam, the foam can also be administered in divided doses: one at bedtime and the other during the night (after evacuation of the first single dose) or in the early morning. The best results are obtained when the intestine is evacuated prior to administration of Salofalk^®.

In general, an acute episode of a mild ulcerative colitis subsides after 4-6 weeks. It is recommended to continue the maintenance therapy with an oral mesalazine preparation e.g. Salofalk gastro-resistant prolonged release granules at a dosage recommended for this preparation.

Children below 12 years of age:

Salofalk rectal foam should not be used in children below 12 years of age because of insufficient experience with the rectal foam in this age group.

Salofalk^®is contraindicated 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 ulcers

- haemorrhagic diathesis

Salofalk should not be used for the treatment of children below the age of 12 years.

Caution:

Asthmatics should be treated with care with Salofalk^®since sulphite contained in the foam may cause hypersensitivity reactions.

Blood tests (differential blood counts; 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 is 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.

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

Special notes:

In isolated cases hypersensitivity reactions principally in the form of respiratory problems may be experienced also by non-asthmatics due to the content of sulphite. This medicine contains propylene glycol that may cause lactic acidosis, hyperosmolality, haemolysis and CNS depression. Slight to mild skin irritation due to propylene glycol may occur. This medicine contains cetostearyl alcohol that may cause local skin reactions (e.g contact dermatitis).

Specific interaction studies have not been performed.

Interactions may occur during treatment with Salofalk 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 gastro-intestinal 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.

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

There are no adequate data from the use of Salofalk rectal foam in pregnant women.

However, data on a limited number of exposed pregnancies after oral application of mesalazine indicate no adverse effect on pregnancy or on the health of the fetus/newborn child. To date no other relevant epidemiological data are available. No animal reproductive studies with Salofalk rectal foam have been performed.

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

Salofalk rectal foam should not be used during pregnancy unless the potential benefit outweighs the possible risk.

N-acetyl-mesalazine (N-Ac-5-ASA) and to a lesser degree mesalazine are excreted in breast milk. Only limited experience during lactation in women after oral application is available to date. Hypersensitivity reactions like diarrhoea can not be excluded.

Therefore, Salofalk rectal foam is not recommended in breast-feeding women. If treatment is necessary, breast-feeding should be discontinued.

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

Special note:

Care should be taken when administering Salofalk to patients with diminished renal function.

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:

Aminosalicylic acid and similar agents mesalazine 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 may also function as a radical scavenger of reactive oxygen compounds. Mesalazine acts predominantly locally at the gut mucosa and in the submucus 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.

General considerations of mesalazine:

Absorption:

Mesalazine absorption is highest in the 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%, dependant 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 Foam Specific:

Distribution:

A combined pharmacoscintigraphic / pharmacokinetic study showed that spreading of Salofalk Foam is homogeneous and fast, and is almost complete within 1 hour. It reaches the gut regions rectum, sigmoid colon, and left-sided colon in dependence of extension of inflammation.

Absorption:

Absorption of mesalazine is fast, and peak plasma concentrations for mesalazine and its metabolite N-Ac-5-ASA are reached at about 4 hours. However, plasma concentrations of a 2g mesalazine rectal dose of foam are about comparable with an 250mg oral dose mesalazine, reaching maximum concentrations of about 0.4 μg/ml. Pre-systemic metabolisation is fast, and N-Ac-5-ASA reaches its maximum plasma concentrations also at about 4 hours, like mesalazine, but plasma concentrations are about 4-5 times higher, about 2μg/ml.

With the exception of a local tolerance study in dogs, which showed good rectal tolerance, no preclinical studies have been performed with Salofalk Foam.

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.

Sodium metabisulphite (E223),

cetostearyl alcohol,

polysorbate 60,

disodium edetate,

propylene glycol,

Propellants:

propane,

n-butane,

isobutane.

Not applicable

3 years.

After first actuation: 12 weeks.

Do not store above 25^oC. Do not refrigerate or freeze. This is a pressurised container, containing 3.75% by mass of inflammable propellant. It should be kept away from any flames, sparks or incandescent material including cigarettes. It should be protected from direct sunlight and temperatures over 50°C and must not be pierced or burned even when empty.

Aluminium pressurised container with metering valve containing 80g (14 actuations) of suspension together with 14 PVC applicators coated with white soft paraffin and liquid paraffin for administration of the foam.

Any unused product waste material should be disposed of in accordance with local requirements.

Dr. Falk Pharma GmbH

Leinenweberstr. 5

P.O. Box 6529

D-79108 Freiburg

Germany

Phone: +49 (0) 761 1514-0

PL 08637/0003

October 2006

July 2009