SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Salofalk lg/actuation Rectal Foam.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 actuation contains:

Mesalazine 1.0 g

Excipients with known effect: cetostearyl alcohol, propylene glycol and sodium metabisulphite

For the full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Rectal foam.

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

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

4.2 Posology and method of administration

Method of Administration: rectal.

Adults:

Two administrations once a day at bedtime. Salofalk rectal foam should be used at room temperature (between 20 and not more than 30°C; see also section 6.4. 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activation depending upon need (see below) the applicator should be held in position for 10-15 seconds before being withdrawn from the rectum.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:

There is little experience and only limited documentation for an effect in children.

4.3 Contraindications

Salofalk is contraindicated in cases of:

-    known hypersensitivity to salicylates or to any of the excipients listed in section 6.1

-    severe impairment of hepatic or renal function

Caution:

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

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 three months. If additional symptoms occur, these tests should be performed immediately.

Caution is recommended in patients with impaired hepatic function.

Salofalk 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.

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 intolerance reactions such as abdominal 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).

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 rectal foam 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.

No animal studies with Salofalk rectal foam have been performed.

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 rectal foam 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 rectal foam 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 rectal foam has no or negligible influence on the ability to drive and use machines

4.8 Undesirable effects

Organ Class System	Frequency According to MedDRA Convention
	Common (>1/100, < 1/10)	Uncommon (>1/1,000, <1/100)	rare (>1/10,000, <1/1,000)	very rare (< 1/10,000)
General disorders and administration site conditions	Abdominal distension	Anal discomfort; application site irritation, painful rectal tenesmus
Blood and lymphatic system disorders				Altered blood counts (aplastic anaemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia)
Nervous system disorders			Headaches, 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 pancreatits
Renal and urinary disorders				Impairment of renal function including acute and chronic interstitial nephritis and renal insufficiency
Skin and subcutaneous tissue disorders				Alopecia
Musculoskeletal				Myalgia, arthralgia

and connective tissue disorders
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)

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 national reporting system, 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:

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.

5.2 Pharmacokinetic properties.

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 Rectal Foam Specific:

Distribution:

A combined pharmacoscintigraphic / pharmacokinetic study showed that spreading of Salofalk rectal 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 250 mg oral dose mesalazine, reaching maximum concentrations of about 0.4 pg/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 2pg/ml.

5.3 Preclinical safety data

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

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sodium metabisulphite (E223), cetostearyl alcohol, polysorbate 60, disodium edetate, propylene glycol,

Propellants:

propane,

n-butane,

isobutane.

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

After first actuation: 12 weeks.

6.4 Special precautions for storage

Do not store above 30^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.

6.5 Nature and contents of container

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.

Package sizes:

Package with 1 spray can Salofalk 1g/actuation rectal foam containing 80g suspension (14 actuations)

Bundle pack with 4 spray cans Salofalk 1g/actuation rectal foam containing 80g suspension each

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

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

7    MARKETING AUTHORISATION HOLDER

Dr. Falk Pharma GmbH Leinenweberstr. 5 79108 Freiburg Germany

Phone: +49(0)761 1514-0

8. MARKETING AUTHORISATION NUMBER

PL 08637/0003

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/10/2006

10 DATE OF REVISION OF THE TEXT

11/11/2013