Salofalk^® 250mg Tablets

Each tablet of Salofalk 250mg gastro-resistant tablets contains 250mg mesalazine.

Excipients: Sodium carbonate

For a full list of excipients, see section 6.1

Gastro-resistant tablet

Appearance: Round, butter-yellow to ochre, gastro-resistant tablets, matt with smooth surface; they are not scored.

Treatment of mild to moderate acute exacerbations of ulcerative colitis and for the maintenance of remission of ulcerative colitis

Method of Administration: Oral

Adults and elderly:

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

For treatment of acute episodes: 1.5g to 3.0g mesalazine daily in three divided doses (six to 12 tablets daily in three divided doses).

For the maintenance of remission: 1.5g mesalazine in three divided doses (six tablets daily in three divided doses – two 250mg tablets three times a day).

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: 75mg/kg/day in divided doses. The total dose should not exceed the maximum dose for adults.

Maintenance treatment: To be determined individually, starting with 15-30 mg/kg/day in divided doses. The total dose should not exceed the recommended dose for adults.

It is generally recommended that half the adult dose may be given to children up to a body weight of 40kg and the normal adult dose to those above 40kg.

General instructions for use:

Salofalk 250mg 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 250mg 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 1.5g mesalazine/day (adults and adolescents with a body weight over 40kg) or 0.75g mesalazine/day (children/adolescents).

Salofalk 250mg Tablets are contraindicated in cases of:

• Known hypersensitivity to salicylates or any of the excipients.

• 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 250mg 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 250mg 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 250mg tablets. Should Salofalk 250mg 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 250mg tablets were excreted undissolved in the stool, due to an excessively rapid intestinal passage.

1 Salofalk 250 mg tablet contains 48 mg sodium. This must be taken into consideration in patients on a sodium-controlled (low-sodium/low-salt) diet.

Specific interaction studies have not been performed.

In patients who are concomitantly treated with azathioprine, 6-mercaptopurine or or thioguaninea 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.

There are no adequate data from the use of Salofalk 250mg tablets in pregnant women. However, data on a limited number of exposed pregnancies indicate no adverse effect of mesalazine on the 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 (2-4g, 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 250mg tablets 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 women is available to date. Hypersensivity reactions such as diarrhoea in the infant cannot be excluded. Therefore, Salofalk 250mg tablets 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.

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

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: 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 250mg tablets are coated with Eudragit L; they are thus gastro-resistant and release of mesalazine is pH-dependent.

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 breast milk mainly as N-Ac-5-ASA.

Salofalk 250mg tablet specific:

Distribution

A combined pharmacoscintigraphic/pharmacokinetic study in patients showed that Salofalk 250mg, gastro-resistant tablets, dissolve after approximately 3-4 hours in the ileum if they are taken concurrently with food (test meal). The median gastric emptying time was approximately 3 hours. After approximately 7 hours, the tablets reached the colon.

In a further study in volunteers, the duodeno-ileal transit time was approximately 3 hours, peak luminal 5-ASA concentrations being measured in the ileum 7–8 hours after concurrent administration of the tablets with the test meal. Approximately 75% of the mesalazine dose reached the colon in non-metabolised form.

Absorption

Release of mesalazine from Salofalk 250mg, gastro-resistant tablets, begins after a lag-phase of approximately 3–4 hours. Peak plasma concentrations are reached after approximately 5 hours (ileocoecal region) and, with 3 x 500 mg mesalazine/ day (3 x 2 Salofalk 250mg) under steady-state conditions, are 2.1 ± 1.7 µg/ml for mesalazine and 2.8 ± 1.7 µg/ml for the metabolite, N-Ac-5-ASA.

Elimination

In long-term therapy with Salofalk 250mg and with a daily dose of 500 mg mesalazine 3 times daily (steady-state conditions), the total renal elimination rate of mesalazine and N-Ac-5-ASA was approximately 55% (24-hour value after administration of last dose). The non-metabolised mesalazine fraction was approximately 5%. The elimination half-life was 0.7–2.4 hours (mean 1.4 0.6 hours) at a dose of 500 mg mesalazine, 3 times daily

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 carbonate, glycine, povidone, microcrystalline cellulose (E460), colloidal anhydrous silica, calcium stearate, hydroxypropylmethylcellulose (E464), methacrylic acid copolymer (Eudragit L), talc, titanium dioxide (E171), iron oxide (E172), polyethylene glycol, polymethacrylate (Eudragit E).

Not applicable

3 years

No special precautions for storage

Orange PVC/PVDC/AI blister strips packed in cartons containing 10, 100 or 300 tablets.

Not all pack sizes may be marketed.

No special requirements

Dr Falk Pharma UK Ltd

Bourne End Business Park

Cores End Road

Bourne End

Buckinghamshire

SL8 5AS

PL 10341/0004

13 September 1991

March 2012