Salofalk

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

Composition:

Active substance: mesalazine;

1 suppository contains 1000 mg of mesalazine (5-aminosalicylic acid);

Excipient: hard fat.

Pharmaceutical form. Rectal suppositories.

Main physicochemical properties: light beige-colored suppositories, torpedo-shaped, with smooth, even, and undamaged surface. During storage, a white coating may form on the surface due to recrystallization of hard fats.

Pharmacotherapeutic group.

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

ATC code A07EC02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

The mechanism of anti-inflammatory action is unknown. In vitro studies 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 also act as a scavenger of reactive oxygen species radicals.

Pharmacodynamic effect

After rectal administration, mesalazine acts predominantly locally on the intestinal mucosa and submucosal layers. The clinical efficacy and safety of Salofalk 1000 mg suppositories were evaluated in phase III multicenter clinical trials involving 403 patients with endoscopically and histologically confirmed mild to moderate ulcerative proctitis. The mean disease activity index (DAI) at baseline was 6.2 ± 1.5 (range: 3–10). Patients were randomized to treatment with either one Salofalk 1000 mg suppository daily (the "1000×1" group) or three Salofalk 500 mg suppositories daily (the "500×3" group) for 6 weeks. The primary efficacy criterion was achievement of clinical remission, defined as a DAI < 4, at the final visit or at study drug discontinuation. According to the per-protocol analysis, 87.9% of patients in the "1000×1" group and 90.7% in the "500×3" group were in clinical remission (intention-to-treat analysis results: "1000×1" group: 84.0%; "500×3" group: 84.7%). The mean change in DAI from baseline was -4.7 in both groups. No serious treatment-related adverse events were observed.

Pharmacokinetics.

General properties of mesalazine

Absorption

Mesalazine absorption is highest in the proximal intestine and lowest in the distal intestine.

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. 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 in feces (major portion), in urine (ranging between 20% and 50%, depending on the route of administration, pharmaceutical formulation, and mesalazine release mechanism), 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.

Specific characteristics of Salofalk 1000 mg rectal suppositories

Distribution

A scintigraphic study using technetium-labeled Salofalk 500 mg suppositories showed a peak dispersion of the melted suppository at body temperature within 2–3 hours. The dispersion is primarily confined to the rectum and rectosigmoid region. Therefore, Salofalk 1000 mg suppositories are particularly suitable for the treatment of proctitis (ulcerative colitis of the rectum).

Absorption

In healthy subjects, the mean plasma concentration of 5-ASA after a single rectal dose of 1000 mg mesalazine (one Salofalk 1000 mg suppository) was 192±125 ng/mL (range: 19–557 ng/mL); the plasma concentration of the main metabolite, N-acetyl-5-ASA, was 402±211 ng/mL (range: 57–1070 ng/mL). The maximum plasma concentration of 5-ASA was reached at 7.1±4.9 hours (range: 0.3–24 hours).

Elimination

In healthy subjects, approximately 14% of the administered dose of 5-ASA is excreted in urine within 48 hours after a single rectal dose of 1000 mg mesalazine (one Salofalk 1000 mg suppository).

Clinical characteristics.

Indications.

Treatment of exacerbations of ulcerative colitis limited to the rectum (ulcerative proctitis).

Contraindications.

Hypersensitivity to mesalazine, to any of the components of the medicinal product or to salicylates; active gastric or duodenal ulcer; severe hepatic and/or renal impairment; haemorrhagic diathesis.

Interaction with other medicinal products and other forms of interaction.

No specific interaction studies with other medicinal products have been conducted.

When treating simultaneously with Salofalk and azathioprine, 6-mercaptopurine or thioguanine, the possible enhancement of the myelosuppressive effect of azathioprine, 6-mercaptopurine or thioguanine should be taken into account.

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

Special precautions for use

The physician should decide to perform blood tests (complete blood count; liver function parameters such as ALT or AST; serum creatinine) and urine tests (dipstick testing, sediment) during and after treatment. Tests should be performed approximately 14 days after the start of treatment, followed by 2–3 additional tests at 4-week intervals.

If test results are normal, routine monitoring can be carried out every 3 months. However, if additional symptoms occur, urgent testing is required.

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

Mesalazine should not be used in patients with impaired renal function. If renal function deteriorates during treatment, mesalazine-induced nephrotoxicity should be considered. In such cases, use of Salofalk 1000 mg suppositories 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 during treatment.

Mesalazine may cause red-brown discoloration of urine after contact with sodium hypochlorite-based bleach (e.g., toilets cleaned with sodium hypochlorite present in certain bleaching agents).

Very rare cases of serious blood dyscrasias associated with mesalazine use have been reported. Hematological investigations should be performed if patients experience unexplained bleeding, bruising, purpura, anemia, fever, or pharyngolaryngeal pain. Salofalk 1000 mg suppositories should be discontinued immediately if blood dyscrasia is suspected or confirmed.

Rare cases of hypersensitivity reactions affecting the heart (myocarditis and pericarditis) caused by mesalazine have been reported. In such cases, use of Salofalk 1000 mg suppositories should be discontinued immediately.

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

Severe 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 in association with mesalazine therapy. Mesalazine should be discontinued at the first sign or symptom 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 who have hypersensitivity reactions to drugs containing sulfasalazine should be under medical supervision from the beginning of treatment with mesalazine. If acute intolerance symptoms such as seizures, acute abdominal pain, fever, severe headache, or rash occur, therapy with Salofalk 1000 mg suppositories should be discontinued immediately.

Use during pregnancy or breastfeeding

Pregnancy

There are no adequate 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. To date, there are no other epidemiological data available for this drug. In only one case, neonatal renal failure was reported after prolonged use of high-dose mesalazine (2–4 g orally) during pregnancy.

Animal studies with oral mesalazine administration showed no direct or indirect adverse effects on pregnancy, embryonic/fetal development, parturition, or postnatal development.

Salofalk 1000 mg suppositories should be used during pregnancy only if the expected benefit outweighs the potential risk.

Lactation

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 1000 mg suppositories should be used during breastfeeding only if the expected benefit to the mother outweighs the potential risk to the infant. If diarrhea develops in the breastfed infant, breastfeeding should be discontinued.

Ability to affect reaction speed when driving or operating machinery

Mesalazine has no effect or only a negligible effect on the ability to drive or operate machinery.

Method of administration and dosage.

This medicinal product is intended for rectal use only.

Salofalk 1000 mg suppositories should preferably be administered in the evening before bedtime.

The desired therapeutic effect can only be achieved with regular and continuous use of Salofalk 1000 mg rectal suppositories.

The duration of treatment is determined by a physician.

Adults and elderly patients

One Salofalk 1000 mg suppository is administered rectally once daily (equivalent to 1000 mg of mesalazine per day).

Children. There is insufficient data on the use of this medicinal product in children.

Overdose.

There are reports of rare cases of overdose (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.

Side effects

In clinical studies involving 248 participants, adverse reactions were observed in approximately 3% of patients treated with Salofalk 1000 mg rectal suppositories. The most frequently reported adverse reactions were headache (approximately 0.8%) and gastrointestinal reactions (constipation in approximately 0.8% of cases; nausea, vomiting, and abdominal pain each occurring in 0.4% of cases).

The following adverse reactions have been observed with mesalazine administration:

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

Severe undesirable 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 precautions for use").

Photosensitivity

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

Reporting of suspected adverse reactions

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

Shelf life. 3 years.

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

Storage conditions.

Keep out of the reach of children. Store at a temperature not exceeding 30 °C. Store in the original packaging to protect from light.

Packaging.

5 suppositories per strip, 2 or 6 strips per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Dr. Falk Pharma GmbH.

Manufacturer's address and location of operations.

Leinenweberstrasse 5, 79108 Freiburg Im Breisgau, Germany.