Mondex

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MONDEX®

Composition:

Active substance: mesalazine;

1 suppository contains 1000 mg of mesalazine;

Excipient: hard fat.

Pharmaceutical form. Suppositories.

Main physico-chemical properties: torpedo-shaped suppositories ranging in color from light pink or light brown to greyish-brown or greyish-pink.

Pharmacotherapeutic group. Gastrointestinal tract and metabolism. Antidiarrheals, intestinal antiinflammatory/antimicrobials. Intestinal antiinflammatory agents. Aminosalicylic acid and related agents. Mesalazine. ATC code A07EC02.

Pharmacological properties.

Pharmacodynamics.

Mesalazine is the active component of sulfasalazine, which is used for the treatment of ulcerative colitis and Crohn's disease.

The therapeutic properties of mesalazine following oral and rectal administration are primarily due to its local action on inflamed areas of the intestine rather than systemic effects. Available data indicate that the severity of intestinal inflammation in patients with ulcerative colitis is reversibly correlated with mesalazine concentration in the intestinal mucosa.

In patients with inflammatory bowel diseases, increased leukocyte migration, abnormal cytokine production, elevated production of arachidonic acid metabolites (particularly leukotriene B4), and increased formation of free radicals in inflamed intestinal tissues are observed.

The mechanism of action of mesalazine is not fully understood, although mechanisms such as stimulation of gamma-form peroxisome proliferator-activated receptors (PPAR-γ) and inhibition of nuclear factor kappa-B (NF-κB) in the intestinal mucosa may be involved. The pharmacological effect of mesalazine observed in in vitro and in vivo studies includes inhibition of leukocyte chemotaxis, reduction in the production of cytokines and leukotrienes, and neutralization of free radicals. Although not definitively established, these processes described above are believed to play a key role in the clinical efficacy of mesalazine.

Pharmacokinetics.

General properties of mesalazine

Absorption

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

Metabolism

Mesalazine is metabolized presystemically in the intestinal mucosa and systemically in the liver into pharmacologically inactive N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA). Acetylation appears to be independent of the acetylator phenotype of the patient. 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 mainly in feces (primary route), in urine (ranging between 20% and 50%, depending on the route of administration, pharmaceutical form, and mesalazine release mechanism), and in bile (minor fraction). Renal excretion occurs predominantly as N-Ac-5-ASA. Approximately 1% of the total orally administered dose of mesalazine is excreted in breast milk, primarily as N-Ac-5-ASA.

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to salicylates or to any of the components of the medicinal product;
• severe hepatic and/or renal insufficiency;
• peptic ulcer of the stomach and duodenum in the stage of exacerbation;
• hemorrhagic diathesis.

Interaction with other medicinal products and other types of interactions.

No specific studies on the interaction of mesalazine in the suppository dosage form with other medicinal products have been conducted.

If treatment with Mondex® and azathioprine, 6-mercaptopurine, or thioguanine is administered simultaneously, possible enhancement of the myelosuppressive effect of azathioprine, 6-mercaptopurine, or thioguanine should be taken into account. The mechanism of this interaction has not been fully elucidated. It is recommended to regularly monitor leukocyte levels and adjust thiopurine doses accordingly.

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

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

Special precautions for use.

Monitoring of blood and urine parameters

At the physician's discretion, laboratory tests of blood (complete blood count and biochemical blood analysis (ALT/AST; creatinine)) and urine (test strips, sediment) should be performed during and after treatment. Tests are generally recommended approximately 14 days after the start of treatment, followed by 2–3 additional tests at 4-week intervals. If laboratory results remain within normal limits, routine monitoring may be conducted every 3 months. However, if additional symptoms occur, laboratory tests should be performed urgently.

Blood disorders

Very rare cases of serious blood dyscrasias associated with mesalazine use have been reported. Hematological investigations should be performed in patients presenting with unexplained bleeding, bruising, purpura, anemia, fever, or pharyngolaryngeal pain. The medicinal product should be discontinued immediately if blood dyscrasia is suspected or confirmed.

Patients with hepatic impairment

Mesalazine (Mondex®) should be used with caution in patients with impaired liver function.

Patients with renal impairment

Mondex® should not be used in patients with renal impairment. Renal function should be monitored during treatment, as mesalazine-induced nephrotoxicity may occur. If renal function deteriorates during therapy, the medicinal product should be discontinued immediately.

Nephrolithiasis

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

Patients with pulmonary disorders

Patients with pulmonary disorders, particularly asthma, should be closely monitored during treatment with Mondex®.

Severe cutaneous adverse reactions

Severe skin adverse reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), Stevens–Johnson syndrome, and toxic epidermal necrolysis, have been reported in association with mesalazine therapy. Mesalazine treatment should be discontinued at the first sign of severe skin reactions such as skin rash, mucosal lesions, or any other signs of hypersensitivity.

Hypersensitivity

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

Rare cases of mesalazine-induced cardiac hypersensitivity reactions (myocarditis and pericarditis) have been reported. In such cases, the medicinal product should be discontinued immediately.

Change in urine color

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

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.

Use during pregnancy or breastfeeding.

Pregnancy

There are inadequate data on the use of mesalazine suppositories in pregnant women. However, limited data from a small number of pregnant women suggest no adverse effects of mesalazine on pregnancy outcome or fetal or neonatal health. Currently, there are no other epidemiological data available specifically for mesalazine suppositories. In one case, neonatal renal failure was reported after prolonged use of high-dose mesalazine (2–4 g orally) during pregnancy. Blood disorders (pancytopenia, leukopenia, thrombocytopenia, and anemia) have been observed in newborns whose mothers received mesalazine treatment during pregnancy.

Limited published data on mesalazine indicate no increased overall risk of congenital malformations. Some data suggest an increased incidence of preterm birth, stillbirth, and low birth weight; however, these adverse pregnancy outcomes are also associated with active inflammatory bowel disease.

Animal studies with oral mesalazine have not shown any direct or indirect adverse effects on pregnancy, embryonic/fetal development, parturition, or postnatal development.

Mondex® should be used during pregnancy only if the expected benefit outweighs the potential risk.

Breastfeeding

N-acetyl-5-aminosalicylic acid and, to a lesser extent, mesalazine are excreted in breast milk. Experience with use in breastfeeding women is currently limited. Hypersensitivity reactions such as diarrhea in the breastfed infant cannot be excluded. Therefore, Mondex® 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.

Fertility

Animal studies have shown no effect of mesalazine on fertility in males or females.

Ability to drive and use machines.

The use of Mondex® has no effect or only a negligible effect on the ability to drive or operate machinery.

Method of Administration and Dosage

The medicinal product Mindex® is intended for rectal use only. Suppositories should preferably be administered in the evening before bedtime. The desired therapeutic effect can only be achieved with regular and continuous use of this medicinal product. The duration of treatment is determined by the physician.

Adults and elderly patients

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

Children

There are 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 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.

Due to the pharmaceutical formulation of mesalazine, the risk of overdose is low.

Since mesalazine is an aminosalicylate, symptoms typical of salicylate poisoning may occur, including acid-base disturbances, pulmonary hyperventilation, dehydration due to sweating and vomiting, and hypoglycemia. Treatment of overdose: in cases of acidosis or alkalosis – restoration of acid-base and electrolyte balance; in dehydration – rehydration; in hypoglycemia – administration of glucose. Additionally, intravenous infusion of electrolyte solutions should be performed to increase diuresis. Close monitoring of kidney function is required.

Adverse Reactions

The most commonly observed adverse reactions during clinical trials were headache, constipation, nausea, vomiting, and abdominal pain.

The adverse reactions listed below are categorized by organ systems and frequency: common (> 1/100, < 1/10), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), and not known (frequency cannot be estimated based on available data).

Blood and lymphatic system disorders: very rare – aplastic anemia, agranulocytosis, pancytopenia, neutropenia, leukopenia, thrombocytopenia.

Nervous system disorders: rare – headache, dizziness; very rare – peripheral neuropathy; not known – idiopathic intracranial hypertension*.

Cardiac and vascular disorders: rare – myocarditis, pericarditis.

Respiratory, thoracic and mediastinal disorders: very rare – allergic and fibrotic lung reactions (including dyspnea, cough, bronchospasm, alveolitis, pulmonary eosinophilia, pulmonary infiltration, pneumonitis).

Gastrointestinal disorders: rare – abdominal pain, diarrhea, bloating, nausea, vomiting, constipation; very rare – acute pancreatitis.

Renal and urinary disorders: very rare – renal dysfunction (including interstitial nephritis* (acute and chronic), renal failure); frequency not known – nephrolithiasis*.

Skin and subcutaneous tissue disorders: common – rash, pruritus; rare – photosensitivity reactions**; very rare – alopecia; frequency not known – drug-induced eosinophilia with systemic symptoms (DRESS syndrome)***, Stevens–Johnson syndrome***, toxic epidermal necrolysis***.

Musculoskeletal and connective tissue disorders: very rare – myalgia, arthralgia, cramps.

Immune system disorders: very rare – hypersensitivity reactions, including allergic rash, drug fever, lupus-like syndrome, pancolitis, Quincke's edema.

Hepatobiliary disorders: very rare – changes in liver function tests (elevated transaminase levels and cholestatic parameters), hepatitis, cholestatic hepatitis, liver failure.

Reproductive system disorders: very rare – oligospermia (reversible).

* For further information, see section "Special Warnings and Precautions for Use".

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

*** Severe skin adverse reactions, including drug-induced eosinophilia with systemic symptoms (DRESS syndrome), Stevens–Johnson syndrome, and toxic epidermal necrolysis, have been reported in association with mesalazine treatment (see section "Special Warnings and Precautions for Use").

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

5 suppositories per strip. 2 or 6 strips per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Kusum Healthcare Pvt Ltd.

Manufacturer's address and location of operations.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.