Salofalk

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SALOFALK® (SALOFALK)

Composition:

Active substance: mesalazine;

1 tablet contains 250 mg of mesalazine (5-aminosalicylic acid);

Excipients: anhydrous sodium carbonate, glycine, povidone (K25), microcrystalline cellulose, anhydrous colloidal silicon dioxide, calcium stearate, hypromellose, methacrylate copolymer (type A), talc, titanium dioxide (E 171), yellow iron hydroxide (E 172), macrogol 6000, acrylate copolymer.

1 tablet contains 500 mg of mesalazine (5-aminosalicylic acid);

Excipients: anhydrous sodium carbonate, glycine, povidone (K25), microcrystalline cellulose, anhydrous colloidal silicon dioxide, calcium stearate, sodium croscarmellose, hypromellose, methacrylate copolymer (type A), talc, titanium dioxide (E 171), yellow iron oxide (E 172), macrogol 6000, acrylate copolymer.

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties:

250 mg: smooth, round tablets of oily-yellow to ochre colour with a non-polished surface;

500 mg: oily-yellow to ochre coloured, non-glossy, elongated tablets with a smooth surface and no visible cracks.

Pharmacotherapeutic group.

Alimentary tract and metabolism. Antidiarrheals, intestinal antiinflammatory/antimicrobials. Intestinal antiinflammatory agents. Aminosalicylic acid and related agents. Mesalazine.

ATC code A07EC02.

Pharmacological Properties

Pharmacodynamics

The mechanism of the anti-inflammatory action is unknown. In vitro study results suggest that inhibition of lipoxygenase may play a certain role.

An effect on prostaglandin concentrations in the intestinal mucosa has also been demonstrated.

Mesalazine (5-aminosalicylic acid/5-ASA) may bind free radicals.

Following oral administration, mesalazine acts predominantly locally on the intestinal mucosa and submucosa from the lumen side of the gut. Therefore, it is important that mesalazine is available at the sites of inflammation. Systemic bioavailability and plasma concentrations are thus not relevant for the therapeutic effect and are more likely factors related to safety. Salofalk tablets are resistant to gastric juice, and mesalazine is released in a pH-dependent manner due to the Eudragit L coating.

Preclinical data based on conventional safety, pharmacology, genotoxicity, carcinogenicity (in rats), and reproductive toxicity studies do not indicate any special hazard for humans.

Renal toxicity (papillary necrosis and damage to the epithelium of the proximal tubules (pars convoluta) or the entire nephron) has been observed in toxicity studies following repeated high oral doses of mesalazine. The clinical relevance of these findings is unknown.

Pharmacokinetics

General properties of mesalazine

Absorption

Absorption of mesalazine is highest in the proximal part of the intestine and lowest in the distal part.

Biological transformation

Mesalazine is metabolized both presystemically in the intestinal mucosa and in the liver to the pharmacologically inactive metabolite N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Acetylation appears to be independent of the patient's acetylator phenotype. Some acetylation also occurs due to bacterial activity in the colon. Protein binding of mesalazine and N-Ac-5-ASA is 43% and 78%, respectively.

Elimination/Excretion

Mesalazine and its metabolite N-Ac-5-ASA are excreted via feces (main route), kidneys (ranging between 20% and 50%, depending on the type of administration, pharmaceutical form, and release mechanism of mesalazine), and bile (minor portion). Renal excretion occurs predominantly as N-Ac-5-ASA. Approximately 1% of the total orally administered dose of mesalazine is excreted in breast milk, mainly as N-Ac-5-ASA.

Characteristics of Salofalk 250 mg tablets

Distribution

A combined pharmacoscintigraphic/pharmacokinetic study showed that Salofalk 250 mg tablets dissolve in the ileum approximately 3–4 hours after administration with food. The mean gastric residence time is about 3 hours. The tablets reach the colon approximately 7 hours after ingestion.

In another study in volunteers, the duodeno-ileal transit time was approximately 3 hours, while the maximum concentration of 5-ASA in the lumen of the ileum was measured 7–8 hours after tablet intake with food. Approximately 75% of the mesalazine dose reaches the colon in non-metabolized form.

Absorption

Release of mesalazine from Salofalk 250 mg tablets begins after a lag phase of about 3–4 hours. Peak plasma concentration is reached approximately 5 hours after dosing (ileocecal region) and, at steady state with a daily dose of 3 × 500 mg mesalazine (3 × 2 Salofalk 250 mg tablets), amounts to 2.1 ± 1.7 µg/mL for mesalazine and 2.8 ± 1.7 µg/mL for the metabolite N-Ac-5-ASA.

Elimination

During long-term therapy with Salofalk 250 mg tablets at a dose of 500 mg mesalazine three times daily (at steady state), the total renal elimination rate of mesalazine and N-Ac-5-ASA was approximately 55% (within 24 hours after the last dose). The fraction of unchanged mesalazine was about 5%. The elimination half-life ranged from 0.7 to 2.4 hours (mean 1.4 ± 0.6 hours) with a dose of 500 mg mesalazine three times daily.

Characteristics of Salofalk 500 mg tablets

Distribution

A combined pharmacoscintigraphic/pharmacokinetic study showed that Salofalk 500 mg tablets dissolve in the ileum approximately 3–4 hours after administration and reach the descending colon approximately 4–5 hours later. The total transit time through the colon is about 17 hours.

Absorption

Release of mesalazine from enteric-coated Salofalk 500 mg tablets begins after a lag phase of about 3–4 hours. Peak plasma concentration is reached approximately 5 hours after dosing (ileocecal region) and, at steady state with a daily dose of 3 × 500 mg mesalazine (3 × 1 Salofalk 500 mg tablet), amounts to 3.0 ± 1.6 µg/mL for mesalazine and 3.4 ± 1.6 µg/mL for the metabolite N-Ac-5-ASA.

Elimination

Following multiple dosing (3 × 1 Salofalk 500 mg tablet for 2 days; 1 enteric-coated tablet on the third day = study day), the total renal elimination rate of mesalazine and N-Ac-5-ASA over 24 hours was approximately 60%. The fraction of unchanged mesalazine after oral administration was about 10%.

Clinical characteristics.

Indications.

• Ulcerative colitis: treatment of acute episodes and prevention of relapses.
• Crohn's disease: treatment of acute episodes.

Contraindications.

Hypersensitivity to mesalazine, to any component of the drug, or to salicylates; active gastric or duodenal ulcer; severe hepatic and/or renal insufficiency; hemorrhagic diathesis.

Interaction with other medicinal products and other forms of interaction.

No specific studies on drug interactions have been conducted.

During combined therapy with Salofalk and azathioprine, 6-mercaptopurine, or thioguanine, a higher incidence of myelosuppressive effects has been observed in some studies, suggesting a possible interaction, although the mechanism of interaction has not been fully elucidated. Regular monitoring of leukocyte levels is recommended, and the dosing regimen of thiopurines should be adjusted accordingly.

There are data indicating that mesalazine may reduce the anticoagulant effect of warfarin.

A possible enhancement of the hypoglycemic effect of sulfonylurea derivatives and of the toxic effect of methotrexate may occur. The activity of furosemide, spironolactone, sulfonamides, rifampicin, and uricosuric agents (probenecid and sulfinpyrazone) may be weakened. Mesalazine may potentiate the adverse effects of glucocorticoids on gastric mucosa and reduce the absorption of digoxin.

Special precautions for use

Before and during treatment, blood tests (complete blood count; liver function parameters such as ALT or AST; serum creatinine) and urine tests (dipstick testing, sediment) should be performed at the physician's discretion. Monitoring is recommended 14 days after initiation of treatment, followed by two to three checks at 4-week intervals.

If test results are normal, routine monitoring every 3 months is sufficient. However, if additional symptoms develop, tests should be performed urgently.

Use with caution in patients with impaired liver function.

Salofalk should be used with caution in patients with impaired renal function. Renal function should be monitored regularly, including measurement of blood urea nitrogen and serum creatinine levels in patients with proteinuria.

Cases of nephrolithiasis, including formation of stones composed entirely of mesalazine (100 %), have been reported during mesalazine therapy. Adequate fluid intake should be ensured during treatment.

Renal function deterioration during treatment should raise suspicion of mesalazine-induced nephrotoxicity.

Patients with pulmonary disorders, particularly asthma, should be under medical supervision throughout the course of Salofalk tablet treatment.

Severe skin reactions

Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine therapy. Mesalazine should be discontinued at the first signs or symptoms of severe skin reactions, such as skin rash, mucosal lesions, or any other signs of hypersensitivity.

Patients who have experienced hypersensitivity reactions, including seizures, acute abdominal pain, fever, severe headache, and rash, to drugs containing sulfasalazine should be closely monitored from the beginning of Salofalk tablet therapy. If acute intolerance reactions such as seizures, acute abdominal pain, fever, severe headache, or rash occur, treatment should be discontinued immediately.

In rare cases, in patients who have undergone intestinal resection or intestinal surgery in the ileocecal region with removal of the ileocecal valve, intact, undissolved Salofalk 250 mg tablets have been observed in feces due to excessively rapid intestinal transit.

Salofalk, 250 mg tablets. One enteric-coated Salofalk tablet contains 48 mg of sodium, equivalent to 2.4 % of the WHO recommended maximum daily intake of sodium. The maximum daily dose of this medication is equivalent to 42.9 % of the WHO recommended maximum daily sodium intake. Salofalk tablets are considered to have a high sodium content. This should be taken into account by patients on a sodium-restricted diet (low-salt diet).

No dose adjustment is required for elderly patients.

Salofalk, 500 mg tablets. One enteric-coated Salofalk tablet contains 2.1 mmol (49 mg) of sodium, equivalent to 2.5 % of the WHO recommended maximum daily sodium intake. The maximum daily dose of this medication is equivalent to 22 % of the WHO recommended maximum daily sodium intake. Salofalk tablets are considered to have a high sodium content. This should be taken into account by patients on a sodium-restricted diet (low-salt diet).

Use during pregnancy or breastfeeding.

Data on the use of enteric-coated Salofalk tablets in pregnant women are limited. However, available data on mesalazine use in a limited number of pregnant women suggest no adverse effects on pregnancy or fetal/neonatal health. Currently, other epidemiological data on this drug are unavailable. In only one case, following prolonged use of high-dose mesalazine (2–4 g orally) during pregnancy, neonatal renal failure was reported. Cases of blood system disorders (leukopenia, thrombocytopenia, anemia) have been reported in newborns whose mothers received mesalazine.

Animal studies with oral administration of mesalazine did not demonstrate any direct or indirect adverse effects on pregnancy, embryonic/fetal development, parturition, or postnatal development.

Salofalk 250 mg and 500 mg tablets should be used during pregnancy only if the potential benefit outweighs the possible risk.

N-acetyl-5-aminosalicylic acid, and to a lesser extent mesalazine, are excreted in breast milk. Experience with use of the drug in breastfeeding women is limited. Hypersensitivity reactions such as diarrhea in the breastfed infant cannot be excluded. Therefore, Salofalk tablets may be used during breastfeeding only if the potential benefit outweighs the possible risk. If diarrhea develops in the breastfed infant, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery.

No influence on the ability to drive vehicles or operate machinery has been observed. However, if dizziness occurs during treatment, patients should refrain from driving or operating machinery.

Dosage and Administration

Salofalk, 250 mg

Adults and elderly patients

For the treatment of chronic inflammatory bowel diseases (Crohn's disease, ulcerative colitis), both Salofalk 250 mg tablets and Salofalk 500 mg tablets can be used.

If a dosage exceeding 1.5 g of mesalazine per day is required, Salofalk 500 mg tablets are recommended.

Depending on the individual clinical need, the following daily doses are recommended for the treatment of adults:

Children under 6 years of age

Salofalk tablets must not be used in children under 6 years of age. There is limited data on the use of the drug in children aged 6 to 18 years.

Children aged 6 years and older

For acute attacks, depending on the severity of the disease, a dose of 30–50 mg mesalazine/kg body weight/day is prescribed, divided into 3 doses. The maximum dose is 75 mg mesalazine/kg body weight/day. The total daily dose must not exceed the maximum adult dose.

For relapse prevention (ulcerative colitis), the drug is prescribed individually, starting with a dose of 15–30 mg mesalazine/kg body weight/day, divided into 2–3 doses. The total daily dose must not exceed the maximum adult dose.

Children with body weight below 40 kg should receive half the adult dose; children with body weight above 40 kg should receive the standard adult dose.

The following daily doses are recommended for the treatment of children aged 6 years and older:

SALOFALK, 500 mg

If the recommended dose exceeds 1.5 g of mesalazine per day, Salofalk 500 mg tablets are usually used.

Adults and elderly patients

Depending on the clinical need in each individual case, the following daily doses are recommended:

Children under 6 years of age

Salofalk tablets must not be used in children under 6 years of age. Data on the use of the drug in children aged 6 to 18 years are limited.

Children from 6 years of age

For acute episodes, depending on the severity of the disease, a dose of 30\−50 mg mesalazine/kg body weight/day is administered in 3 divided doses. The maximum dose is 75 mg mesalazine/kg body weight/day. The total daily dose must not exceed the maximum daily dose for adults.

For prevention of relapses (ulcerative colitis), the drug is prescribed individually, starting with a dose of 15\−30 mg mesalazine/kg body weight/day, divided into 2\−3 doses. The total daily dose must not exceed the maximum daily dose for adults.

Children with body weight below 40 kg should receive half the adult dose; children with body weight above 40 kg should receive the standard adult dose.

Depending on clinical requirements and the child's body weight (up to 40 kg), a decision should be made on which tablet strength to use: Salofalk 250 mg or Salofalk 500 mg.

General administration instructions

Salofalk tablets should be taken in the morning, at noon, and in the evening, 1 hour before meals. Tablets must be swallowed whole, without chewing, with sufficient fluid.

For both acute inflammatory conditions and long-term treatment to achieve the desired therapeutic effect, Salofalk tablets must be taken regularly and continuously.

The duration of treatment is determined by the physician.

For maintenance of remission in ulcerative colitis, the dose may be reduced to 1.5 g mesalazine per day (adults and children with body weight over 40 kg) or to 0.75 g mesalazine per day (children/adolescents).

Children.

Salofalk tablets must not be used in children under 6 years of age. Data on the use of the drug in children aged 6 to 18 years are limited.

Overdose.

Cases of intoxication and specific antidotes have not been reported to date.

There are reports of overdose incidents (e.g., intentional self-poisoning with high oral doses of mesalazine), which did not indicate renal or hepatic toxicity. There is no specific antidote; treatment should be symptomatic and supportive. If necessary, intravenous electrolyte infusion (forced diuresis) may be administered.

Adverse reactions.

*See section "Special precautions for use".

Fatigue, paraesthesia, methaemoglobinaemia, prolonged diarrhoea, and exacerbation of colitis symptoms may also occur.

The mechanism of development of myocarditis, pericarditis, pancreatitis, nephritis, and hepatitis associated with mesalazine use is unknown; it may have an allergic aetiology.

It should be noted that some of these disorders may be explained by the intestinal inflammation itself.

Serious severe skin reactions have been reported, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), associated with mesalazine treatment (see section "Special precautions for use").

Photosensitivity

More severe reactions have been reported in patients with pre-existing skin disorders such as atopic dermatitis and atopic eczema.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is very 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:

Bundesinstitut für Arzneimittel und Medizinprodukte
(Federal Institute for Medicinal Products and Medical Devices)
Pharmacovigilance Department
Kurt-Georg-Kiesinger-Allee 3
53175 Bonn
www.bfarm.de

Shelf life. 3 years. Do not use after the expiry date stated on the packaging.

Storage conditions. Keep out of the reach and sight of children. Store at temperatures not exceeding 25 °C.

Packaging. 10 tablets per blister; 5 or 10 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Dr. Falk Pharma GmbH.

Manufacturer's address and place of business.

Leinenweberstrasse 5, 79108 Freiburg, Germany.