This information is intended for use by health professionals

1. Name of the medicinal product

Salofalk 1g gastro-resistant tablets

Mesalazine

2. Qualitative and quantitative composition

Each gastro-resistant tablet contains 1g mesalazine.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Gastro-resistant tablets

Yellow to ochre yellow, oblong, biconvex, rounded edges gastro-resistant tablets with smooth surface.

4. Clinical particulars
4.1 Therapeutic indications

For the treatment of acute episodes of mild to moderate ulcerative colitis.

4.2 Posology and method of administration

Posology

Adults

The recommended daily dose for the treatment of acute episodes of mild to moderate ulcerative colitis is one Salofalk 1g tablet three times a day (morning, midday and evening, equivalent to 3g of mesalazine daily).

Paediatric population

There is only limited documentation for an effect in children (age 6-18 years).

Children 6 years of age and older

The dose should be determined individually, starting with 30-50 mg/kg/day in divided doses. Maximum dose: 75mg/kg/day. The total dose should not exceed the maximum adult dose.

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.

In children below 40kg, it appears preferable to use mesalazine preparations of lower strengths (e.g., Salofalk 500mg gastro-resistant tablets or Salofalk 500mg gastro-resistant prolonged-release granules).

Method of administration

Salofalk 1g tablets should be taken 1 hour before meals. They should be swallowed whole, not chewed and taken with plenty of fluid.

Therapy with Salofalk 1g tablets should be administered regularly and consistently in order to achieve the desired therapeutic effect.

Duration of treatment

The duration of use is determined by the physician. Induction of remission is usually achieved within 8 weeks.

Note:

The standard treatment of the maintenance of remission is 500mg mesalazine three times daily. For this indication tablets containing 500mg mesalazine (e.g., Salofalk 500mg gastro-resistant tablets) are available.

4.3 Contraindications

Salofalk 1g tablets are contraindicated in patients with:

- Hypersensitivity to the active substance, salicylates or to any of the excipients listed in section 6.1

- Severe impairment of hepatic or renal function.

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

Caution is recommended in patients with impaired hepatic function.

Salofalk 1g tablets should not be used in patients with impaired renal function. Mesalazine-induced renal toxicity should be considered, if renal function deteriorates during treatment.

Cases of nephrolithiasis have been reported with the use of mesalazine including stones with a 100% mesalazine content. It is recommended to ensure adequate fluid intake during treatment.

Patients with pulmonary disease, in particular asthma, should be very carefully monitored during a course of treatment with Salofalk 1g tablets.

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment.

Mesalazine should be discontinued, at the first appearance of signs and symptoms of severe skin reactions, such as skin rash, mucosal lesions, or any other sign of hypersensitivity.

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 tablets.

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

Note:

In patients who have undergone bowel resection/bowel surgery in the ileocoecal region with removal of the ileocoecal valve, it may happen that Salofalk 1g tablets are excreted undissolved in the stool, due to an excessively rapid intestinal passage.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

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 1g tablets 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 fetus/newborn child. To date no other relevant epidemiologic 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/fetal development, parturition or postnatal development.

Salofalk 1g tablets should only be used during pregnancy if the potential benefit outweighs the possible risk.

Breast-feeding

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 tablets should only be used during breast-feeding if the potential benefit outweighs the possible risk. If the infant develops diarrhoea, the breast-feeding should be discontinued.

4.7 Effects on ability to drive and use machines

Salofalk 1g tablets have no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

The following undesirable effects have been observed after administration of mesalazine:

System Organ Class

Frequency according to MedDRA convention

Common

(≥ 1/100 to <1/10)

Uncommon

(≥ 1/1,000 to <1/100)

Rare

(≥ 1/10,000 to <1/1,000)

Very rare

(< 1/ 10,000)

Not known

(cannot be estimated from the available data)

Blood and lymphatic system disorders

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

Immune system disorders

Hypersensitivity reactions such as allergic exanthema, drug fever, lupus erythematosus syndrome, pancolitis

Nervous system disorders

Headache

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, dyspepsia, flatulence, nausea, vomiting acute pancreatitis

Hepatobiliary disorders

Cholestatic hepatitis

Hepatitis

Skin and subcutaneous tissue disorders

Photosensitivity

Alopecia

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)

Musculoskeletal and connective tissue disorders

Arthralgia

Myalgia

Renal and urinary disorders

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

Nephrolithiasis*

Reproductive system and breast disorders

Oligospermia (reversible)

General disorders

Asthenia, fatigue

Investigations

Changes in liver function parameters (increase in transaminases and parameters of cholestasis), changes in pancreatic enzymes (lipase and amylase increased), eosinophil count increased

* see section 4.4 for further information

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment (see section 4.4).

Photosensitivity

More severe reactions are reported in patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

There are rare data on overdose (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: Intestinal antiinflammatory agents, aminosalicylic acid and similar agents

ATC code: A07EC02

Mechanism of action

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.

Pharmacodynamic effects

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 1g tablets are coated with Eudragit L; they are thus gastro-resistant and release of mesalazine is pH-dependent.

5.2 Pharmacokinetic properties

General considerations of mesalazine

Absorption

Mesalazine absorption is highest in proximal gut regions and lowest in distal gut areas.

Biotransformation

Mesalazine is metabolised pre-systemically both 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 1g tablets specific

Release of mesalazine from Salofalk 1g tablets begins after a lag-phase of approximately 4 hours. Peak plasma concentrations of mesalazine are reached after 8 hours and are 2.5 ± 3.4 µg/ml for mesalazine and 2.5 ± 2.4 µg/ml for the metabolite, N-Ac-5-ASA, after single dose administration.

5.3 Preclinical safety data

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 tubule (pars convoluta) 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

Cellulose, microcrystalline

Povidone K 25

Croscarmellose sodium

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

Methacrylic acid methyl methacrylate copolymer (1:2) (Eudragit S 100)

Calcium stearate [herbal origin]

Talc

Macrogol 6000

Hypromellose

Silica, colloidal anhydrous

Iron oxide yellow (E172)

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Blister: PVC/PVDC (orange-transparent)/aluminium blister foil

Package sizes:

Blister packs with 20, 50, 60, 90,100 and 150 Salofalk 1g tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

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

7. Marketing authorisation holder

Dr. Falk Pharma GmbH

Leinenweberstr. 5

79108 Freiburg

Germany

Tel.: +49 (0)761 1514-0

Fax: +49 (0)761 1514-321

E-mail: [email protected]

www.drfalkpharma.de

8. Marketing authorisation number(s)

PL08637/0027

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 10th May 2017

10. Date of revision of the text

01/2021