Salofalk

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

Composition:

Active substance: mesalazine;

1 enema (60 g of suspension) contains 4.0 g of mesalazine (5-aminosalicylic acid);

Excipients: sodium benzoate (E 211), potassium metabisulfite (E 224), disodium edetate, carbomer 934 P, potassium acetate, xanthan gum, purified water.

Pharmaceutical form. Rectal suspension.

Main physicochemical characteristics: homogeneous suspension, color ranging from very light brown to brown, free from foreign particles.

Pharmacotherapeutic group.

Anti-inflammatory agents used in the treatment of intestinal diseases.

ATC code A07EC02.

Pharmacological properties.

Pharmacodynamics.

The mechanism of anti-inflammatory action is unknown. Results of in vitro studies suggest that inhibition of lipoxygenase may play a certain role.

An effect on the concentration of prostaglandins in the intestinal mucosa has also been demonstrated. Mesalazine (5-aminosalicylic acid/5-ASA) may also act as a scavenger of reactive oxygen species radicals.

After rectal administration, mesalazine acts predominantly locally on the intestinal mucosa and submucosal tissue from the intestinal lumen.

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

Renal toxicity (renal papillary necrosis and damage to the epithelium of proximal tubules (Pars convoluta) or entire nephrons) 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 pharmacologically inactive 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 in feces (main portion), in urine (ranging between 20% and 50%, depending on the mode of administration, pharmaceutical form, and mesalazine release pathway), and in 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 enemas, 4 g/60 ml

Distribution

Scintigraphic studies in patients with mild to moderate active ulcerative colitis showed that the enema fluid distributes primarily in the rectum and sigmoid colon, and to a lesser extent in the descending colon, both at the beginning of treatment and after 12 weeks of therapy.

Absorption and elimination

In a study involving patients with ulcerative colitis in remission, steady-state plasma peak concentrations were 0.92 μg/mL for 5-ASA and 1.62 μg/mL for N-Ac-5-ASA approximately 11–12 hours after administration. Elimination rate was approximately 13% (over 45 hours), with the majority (about 85%) being excreted as the metabolite N-Ac-5-ASA.

Plasma concentrations of 5-ASA and N-Ac-5-ASA in children with chronic inflammation of the large intestine treated with Salofalk, 4 g/60 ml, were 0.5–2.8 μg/mL and 0.9–4.1 μg/mL, respectively.

Clinical characteristics.

Indications.

Treatment of exacerbations of ulcerative colitis (a chronic inflammatory disease of the colon).

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 treatment with Salofalk and azathioprine, 6-mercaptopurine, or thioguanine, a higher incidence of myelosuppressive effects has been observed in some studies, suggesting possible interaction, although the mechanism of interaction has not been fully established. It is recommended to regularly monitor white blood cell counts, and the dosing regimen of thiopurines should be adjusted accordingly.

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

Mesalazine may enhance the hypoglycemic effect of sulfonylurea derivatives and 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.

Special precautions for use.

At the physician's discretion, blood tests (complete blood count; liver function parameters such as ALT or AST; serum creatinine) and urine tests (dipstick testing, sediment analysis) should be performed during and after treatment. Testing is generally recommended approximately 14 days after initiation of therapy, followed by 2–3 additional tests at 4-week intervals.

If test results remain normal, routine monitoring may be conducted every 3 months. However, if additional symptoms develop, urgent testing is required.

Mesalazine should be used with caution in patients with impaired liver function.

Mesalazine enemas should be used cautiously in patients with mild to moderate renal impairment. Renal function should be monitored regularly, including measurement of blood urea nitrogen and creatinine levels, particularly in patients with proteinuria. Worsening renal function during treatment should raise suspicion of mesalazine-induced nephrotoxicity. If renal function deteriorates during therapy, Salofalk should be discontinued immediately.

Cases of nephrolithiasis, including formation of calculi composed of 100% mesalazine, have been reported during mesalazine therapy. Adequate fluid intake should be ensured 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 disinfectants).

Very rarely, serious blood dyscrasias have been reported with mesalazine use. Hematological investigations should be performed if patients develop unexplained bleeding, bruising, purpura, anemia, fever, or pharyngolaryngeal pain. Mesalazine should be discontinued if blood dyscrasia is suspected or confirmed.

Rare cases of cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported with mesalazine. In such cases, mesalazine should be discontinued immediately.

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

Serious skin reactions

Severe cutaneous adverse reactions (SCARs), 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 severe 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 receiving 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 a history of adverse reactions to sulfasalazine-containing drugs should be closely monitored from the beginning of mesalazine therapy. If Salofalk suspension causes acute intolerance reactions such as abdominal cramps, acute abdominal pain, fever, severe headache, or rash, therapy should be discontinued immediately.

Since Salofalk enemas 4 g/60 mL contain potassium metabisulfite, they may provoke allergic-type reactions, including anaphylactic symptoms and bronchospasm, in susceptible individuals, particularly in patients with bronchial asthma or a history of allergies.

As the product contains sodium benzoate, it may cause hypersensitivity reactions, including irritation of the skin, eyes, or mucous membranes.

Use during pregnancy or breastfeeding.

There are inadequate data on the use of mesalazine in pregnant women. However, limited data from a small number of pregnant women suggest no adverse effects of mesalazine on pregnancy or fetal and/or neonatal health. Currently, no further epidemiological data on the drug are available. In only one case, neonatal renal failure was reported after prolonged use of high-dose mesalazine (2–4 g orally) during pregnancy. Cases of hematological disorders (leukopenia, thrombocytopenia, anemia) have been reported in newborns whose mothers used mesalazine during pregnancy.

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

Salofalk enemas 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 in the breastfed infant, such as diarrhea, cannot be excluded. Therefore, Salofalk enemas may be used during breastfeeding only if the expected benefit outweighs the potential risk. If diarrhea develops in the breastfed infant, breastfeeding should be discontinued.

Ability to affect driving and use of machinery.

Mesalazine does not impair the ability to drive or operate machinery. However, if dizziness occurs during treatment, patients should refrain from driving or operating machinery.

Method of Administration and Dosage

Adults and elderly patients

Patients with symptoms of acute inflammation are recommended to administer the contents of one enema (60 g of suspension) rectally once daily in the evening before bedtime.

The best results are achieved if the bowel is cleansed prior to administration of Salofalk enema.

The desired therapeutic effect can only be achieved with regular and consistent use of Salofalk enemas.

The duration of treatment should be determined by a physician.

Instructions for administration of the suspension

Preparation:

• Shake the enema for 30 seconds.
• Remove the protective cap from the applicator.
• Hold the enema by the side surfaces.

Correct position for administration:

• The patient should lie on the left side, extending the left leg and bending the right leg. This facilitates easier administration and enhances effectiveness.

Administration of the enema:

• Insert the tip of the applicator as far as possible into the rectum.
• Slightly raise the bottom of the enema and slowly squeeze.
• Once the enema is empty, slowly withdraw the applicator tip from the rectum.
• The patient should continue lying down for at least 30 minutes to allow the enema contents to distribute throughout the rectum.
• If possible, allow the enema liquid to exert its effect throughout the night.

Children. There is insufficient experience regarding the use of this medicinal product in children.

Overdose

To date, there have been no reports of intoxication or specific antidotes. Cases of overdose have been reported (e.g., intentional self-poisoning by 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 infusion of electrolytes (forced diuresis) may be administered.

Adverse reactions.

*See section "Special precautions".

Severe cutaneous adverse reactions (SCARs), including drug-induced eosinophilia with systemic symptoms (DRESS syndrome), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment (see section "Special precautions").

Photosensitivity

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

Also possible are fatigue, paraesthesia, methaemoglobinaemia, prolonged diarrhoea, and exacerbation of colitis symptoms.

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

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

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

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

Packaging. 60 g of suspension in a enema; 7 enemas in blisters, in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Dr. Falk Pharma GmbH.

Manufacturer's address and place of business.

Leinenweberstrasse 5, 79108 Freiburg im Breisgau, Germany.