Salofalk

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

Composition:

Active substance: mesalazine;

1 sachet (930 mg of granules) contains 500 mg of mesalazine or 1 sachet (1860 mg of granules) contains 1000 mg of mesalazine;

Excipients: microcrystalline cellulose, hypromellose, colloidal anhydrous silicon dioxide, polyacrylate dispersion, magnesium stearate, simethicone emulsion, methacrylate copolymer (type A), triethyl citrate, talc, titanium dioxide (E 171), sodium carboxymethylcellulose, aspartame (E 951), anhydrous citric acid, sweet vanilla flavoring, povidone.

Pharmaceutical form. Gastric-resistant prolonged-release granules.

Main physicochemical properties: rounded particles of elongated or round shape, greyish-white in color, packed in aluminum foil sachets.

Pharmacotherapeutic group.

Gastrointestinal tract and metabolism. Antidiarrheals, intestinal anti-inflammatory/antimicrobial agents. Intestinal anti-inflammatory agents. Aminosalicylic acid and related agents. Mesalazine.

ATC code A07EC02.

Pharmacological properties.

Pharmacodynamics

Pharmacodynamic effect.

Mesalazine, when administered orally, acts predominantly locally on the intestinal mucosa and submucosa from the luminal 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 significant for determining the therapeutic effect, but are more likely factors in assessing safety profile. Salofalk granules are resistant to gastric juice, and mesalazine is released in a pH-dependent manner due to the Eudragit L coating; prolonged release is ensured by the matrix structure of the granules.

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

Renal toxicity (renal 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 acetylator phenotype. Some acetylation also occurs due to the action of colonic bacteria. Plasma protein binding of mesalazine and N-Ac-5-ASA is approximately 43% and 78%, respectively.

Elimination/excretion

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

Specific characteristics of Salofalk granules

Distribution

Due to the granule size of approximately 1 mm, their passage from the stomach to the duodenum occurs rapidly.

A combined pharmacoscintigraphic/pharmacokinetic study showed that the compound reaches the ileocecal region within 3 hours and the ascending colon approximately 4 hours after administration. Total colonic transit time is approximately 20 hours.

Approximately 80% of the orally administered dose is available in the cecum, sigmoid colon, and rectum.

Absorption

Release of mesalazine from Salofalk granules begins after a lag phase of about 2–3 hours. Peak plasma concentration is reached approximately 4–5 hours after administration. Systemic bioavailability of mesalazine after oral administration is approximately 15–25%.

Food intake delays absorption by 1–2 hours but does not alter the extent or rate of absorption.

Elimination

When mesalazine is administered at a daily dose of 3 × 500 mg, the total renal elimination rate of mesalazine and N-Ac-5-ASA at steady state was approximately 25%. The fraction of unchanged mesalazine excreted was about 1% of the oral dose. Terminal elimination half-life after a single dose of Salofalk granules 3*500 mg or 3*1000 mg was 10.5 hours.

Clinical Characteristics.

Indications.

Treatment of mild to moderate exacerbations and prevention of relapses of ulcerative colitis.

Contraindications.

Hypersensitivity to mesalazine, to any component of the medicinal product 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 treatment with Salofalk and azathioprine, 6-mercaptopurine or thioguanine, some studies have shown a higher frequency of myelosuppressive effects, suggesting a possible interaction, although the exact mechanism has not been fully established. Regular monitoring of leukocyte counts is recommended, and the dosage regimen of thiopurines should be adjusted accordingly.

There is evidence that mesalazine may reduce the anticoagulant effect of warfarin.

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

A decreased release of mesalazine from granules may occur due to a reduction in pH caused by bacterial metabolism of lactulose.

Special precautions for use.

The physician should, at his/her discretion, perform blood tests (formed elements; liver function parameters such as ALT or AST; serum creatinine) and urine tests (dipstick testing, sediment) during and after treatment. These tests should be performed approximately 14 days after initiation of therapy, followed by 2–3 additional tests at 4-week intervals. If test results are within normal limits, preventive monitoring may be conducted every three months. In case of appearance of any additional symptoms, tests should be performed urgently.

Use with caution in patients with impaired liver function.

Mesalazine should not be used in patients with impaired renal function. Renal function should be monitored regularly, including measurement of blood urea nitrogen and creatinine levels in patients with proteinuria.

If renal function deteriorates during treatment, mesalazine-induced nephrotoxicity should be considered. In such cases, treatment with Salofalk granules should be discontinued immediately.

Cases of nephrolithiasis, including formation of stones composed of 100% mesalazine, have been reported during mesalazine therapy. Adequate fluid intake is recommended throughout treatment.

Mesalazine may cause red-brown discoloration of urine upon contact with sodium hypochlorite-based bleach (e.g., in toilets cleaned with sodium hypochlorite-containing cleaning agents).

Very rare cases of severe blood dyscrasias associated with mesalazine use have been reported. Hematological investigations should be performed if patients develop unexplained bleeding, bruising, purpura, anemia, fever, or pharyngolaryngeal pain. Salofalk granules should be discontinued if suspicion or confirmation of blood dyscrasia occurs.

Rare cases of hypersensitivity reactions affecting the heart (myocarditis and pericarditis) have been reported with mesalazine. In such cases, Salofalk granules should be discontinued immediately.

Patients with pulmonary disorders, particularly asthma, should be closely monitored during mesalazine therapy.

Serious skin reactions

Serious skin adverse reactions (SSARs), including drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), have been reported with mesalazine therapy. Mesalazine should be discontinued at the first sign of serious skin reactions, such as skin rash, mucosal lesions, or any other signs of hypersensitivity.

Idiopathic intracranial hypertension

Idiopathic intracranial hypertension (pseudotumor cerebri) has been reported in patients treated with mesalazine. Patients should be informed about the signs and symptoms of idiopathic intracranial hypertension, including severe or recurrent headache, visual disturbances, or tinnitus. If idiopathic intracranial hypertension occurs, discontinuation of mesalazine should be considered.

Patients with hypersensitivity reactions to sulfasalazine-containing drugs should be closely monitored from the beginning of mesalazine therapy. If acute intolerance symptoms such as seizures, acute abdominal pain, fever, severe headache, or rash occur, treatment should be discontinued immediately.

Salofalk granules 500 mg and 1000 mg contain 1 mg and 2 mg of aspartame, respectively. Aspartame is a source of phenylalanine and may be harmful to patients with phenylketonuria (PKU). Dose adjustment is not required in elderly patients.

Salofalk granules contain sucrose. This medicinal product should not be used in patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

This medicinal product contains less than 1 mmol sodium (23 mg) per sachet, i.e., it is essentially "sodium-free".

Use during pregnancy or breastfeeding.

Data on mesalazine use in pregnant women are limited; however, available data from a limited number of pregnancies suggest no adverse effects of mesalazine on pregnancy or fetal or neonatal health. Currently, other epidemiological data on the drug are not available. A single case of renal failure in a newborn whose mother had received high-dose mesalazine (2–4 g orally) throughout pregnancy has been reported. Cases of hematological disorders (leukopenia, thrombocytopenia, anemia) in newborns whose mothers used mesalazine have also been reported.

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

Salofalk granules should be used during pregnancy only if the expected benefit outweighs the potential risk.

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

Ability to affect the speed of reactions while driving or operating machinery.

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

Method of Administration and Dosage

Adults and Elderly Patients

Treatment of Acute Exacerbations of Ulcerative Colitis

Take once daily 3 sachets of Salofalk 500 mg or 3 sachets of Salofalk 1000 mg (equivalent to 1.5–3.0 g of mesalazine per day), preferably in the morning, according to individual clinical need.

For convenience, the prescribed daily dose may alternatively be divided into 3 doses (1 sachet of Salofalk 500 mg granules 3 times daily or 1 sachet of Salofalk 1000 mg granules 3 times daily).

Prevention of Relapses of Ulcerative Colitis (Maintenance of Remission)

Take 1 sachet of Salofalk 500 mg 3 times daily, equivalent to 1.5 g of mesalazine per day.

For patients at increased risk of relapse for medical reasons or due to difficulties in adhering to a regimen of three daily doses, the dosing regimen may be changed to 3.0 g of mesalazine as a single daily dose, preferably in the morning.

Children under 6 years of age

Salofalk granules must not be used in children under 6 years of age due to lack of experience with the use of the drug in this age group.

Children aged 6 years and older

Depending on the severity of the disease during exacerbations, administer 30–50 mg mesalazine/kg body weight/day once daily, preferably in the morning, or divide this dose into 3 administrations. Maximum dose: 75 mg/kg body weight/day. The total dose must not exceed the maximum adult dose.

For prevention of relapses (maintenance therapy), a dose of 15–30 mg mesalazine/kg body weight/day should be administered, divided into several doses.

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.

Treatment Duration

Treatment of acute episodes of ulcerative colitis usually lasts 8 weeks. The duration of treatment is determined by the physician.

Salofalk granules must not be chewed. The contents of the "Granu-Stix" sachet 500 mg or 1000 mg should be poured onto the tongue and swallowed with sufficient liquid without chewing.

Both during treatment of acute inflammatory episodes and during long-term therapy, Salofalk granules should be taken regularly and continuously to achieve the desired therapeutic effect.

Children. Salofalk granules must not be used in children under 6 years of age due to lack of experience with the use of the drug in this age group. Data on use in children aged 6–18 years are limited.

Overdose.

There are reports of overdose cases (e.g., intentional self-harm by ingestion of high oral doses of mesalazine), which do not indicate renal or hepatic toxicity. Cases of intoxication and specific antidotes have not been reported to date. No specific antidote exists; treatment should be symptomatic and supportive. If necessary, intravenous electrolyte infusion (forced diuresis) may be administered.

Adverse reactions.

*For more detailed information, see section "Special instructions for use".

Severe skin reactions have been reported, including drug-induced eosinophilia with systemic symptoms (DRESS syndrome), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), associated with mesalazine treatment (see section "Special instructions for use").

Photosensitivity

There have been reports of severe reactions in patients with skin disorders, such as atopic dermatitis and atopic eczema.

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

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

Reporting suspected adverse reactions

Reporting adverse reactions after drug registration is important. It enables ongoing monitoring of the benefit-risk balance of the use of this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Do not use after the expiry date stated on the packaging.

Storage conditions. No special storage conditions required. Keep out of reach of children.

Packaging.

Salofalk, granules. 500 mg:

930 mg granules in "Granu-Stix" sachets; 50 sachets per cardboard box.

Salofalk, granules, 1000 mg:

1860 mg granules in "Granu-Stix" sachets; 50 sachets per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Dr. Falk Pharma GmbH / Dr. Falk Pharma GmbH.

Manufacturer's address and location of operations.

Leinenweberstrasse 5, 79108 Freiburg Im Breisgau, Germany / Leinenweberstrasse 5, 79108 Freiburg Im Breisgau, Germany.