Dr. Falk Pharma UK Ltd

Salofalk 1g Suppositories

Each suppository contains 1 g mesalazine.

For a full list of excipients, see section 6.1

Suppositories

Appearance: light beige coloured, torpedo-shaped suppositories

Treatment of acute mild to moderate ulcerative colitis that is limited to the rectum (ulcerative proctitis).

Adults and elderly:

One Salofalk 1g Suppository once daily (equivalent to 1g mesalazine daily) inserted into the rectum.

Children

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

General instructions for use:

Salofalk 1g Suppositories should be administered preferably at bedtime.

Treatment with Salofalk 1g Suppositories must be administered regularly and consistently, because only in this way can healing be successfully achieved.

The duration of use is determined by the physician.

Salofalk 1g Suppositories are contraindicated in patients with:

- known hypersensitivity to salicylates or the excipient

- severe impairment of hepatic or renal function

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 1g Suppositories 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 1g Suppositories.

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 1g Suppositories. Should Salofalk 1g Suppositories cause acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, severe headache and rash, therapy should be discontinued immediately.

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.

Pregnancy

There are no adequate data on the use of Salofalk 1g Suppositories 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 (2-4 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, embryonic/foetal development, parturition or postnatal development.

Salofalk 1g Suppositories 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 1g Suppositories should only be used during breastfeeding if the potential benefit outweighs the possible risk. If the infant develops diarrhoea, breast-feeding should be discontinued.

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

In clinical studies involving 248 participants, approximately 3% experienced adverse reactions while receiving Salofalk 1g Suppositories. The most commonly reported ADRs were headache, in approximately 0.8%, and gastrointestinal side effects (constipation in approximately 0.8%; nausea, vomiting and abdominal pain in 0.4% each).

The following side effects have been reported with the use of mesalazine:

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.

Pharmacotherapeutic group: Aminosalicylic acid and similar agents

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.

On reaching the intestinal lumen, rectally administered mesalazine has largely local effects on the intestinal mucosa and submucosal tissue.

Clinical efficacy and safety of Salofalk^® 1 g suppositories was evaluated in a multicentre phase III study, which included 403 patients with endoscopically and histologically confirmed mild to moderately active ulcerative proctitis. The mean disease activity index (DAI) at base line was 6.2 ± 1.5 (range: 3 – 10). Patients were randomised to treatment with one Salofalk^® 1 g suppository (1 g OD group) or 3 suppositories containing 0.5 g mesalazine (0.5 g TID group per day for 6 weeks. The primary efficacy variable was clinical remission defined as DAI < 4 at the final visit or withdrawal. At the final per protocol analysis, 87.9% of the patients in the 1 g OD group and 90.7% of the 0.5 g TID group were in clinical remission (Intention-to-treat analysis: 1 g OD group: 84.0%; 0.5 g TID group: 84.7%). The mean change in DAI from baseline was -4.7 in both treatment groups. No drug-related serious AEs occurred.

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 in 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 1g suppositories specific:

Distribution:

Scintigraphic studies with a similar medicinal product, technetium-labelled mesalazine 500mg suppositories showed peak spread of the suppository that had melted due to body temperature after 2 – 3 hours. The spread was limited primarily to the rectum and rectosigmoid junction. It is assumed that Salofalk 1g suppositories act very similar and thus are particularly suitable for treating proctitis (ulcerative colitis of the rectum).

Absorption:

In healthy subjects mean peak plasma concentrations of 5-ASA after a single rectal dose of 1g mesalazine (Salofalk 1 g Suppository) were 192 ± 125 ng/ml (range 19 – 557 ng/ml), those of the main metabolite N-Ac-5-ASA were 402 ± 211 ng/ml (range 57 – 1070 ng/ml). Time to reach the peak plasma concentration of 5-ASA was 7.1 ± 4.9 h (range 0.3 – 24 h).

Elimination:

In healthy subjects, after a single rectal dose of 1g mesalazine (Salofalk 1g Suppository) approx. 14 % of the administered 5-ASA dose were recovered in the urine during 48 hours.

With the exception of a local tolerance study in dogs, which demonstrated good rectal tolerance, no preclinical studies have been performed with Salofalk 1g Suppositories.

Preclinical data on mesalazine 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.

Hard fat

Not applicable.

3 years

Store in the original container in order to protect contents from light.

Do not store above 25°C.

Container (strip): PVC/polyethylene film

Package sizes: 10, 12, 15, 20, 30, 60, 90

Not all package sizes may be marketed.

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

Dr. Falk Pharma GmbH

Leinenweberstr. 5

79108 Freiburg

Germany

Tel: +49 (0)761 1514-0

PA573/4/4

17^th May 2010

01/2012