Pentasa prolonged-release tablets 500 mg No. 50

Instructions for Pentasa extended-release tablets 500 mg No. 50

Composition

active ingredient: mesalazine;

1 tablet contains mesalazine 500 mg;

excipients: povidone, ethylcellulose, magnesium stearate, talc, microcrystalline cellulose.

Dosage form

Extended-release tablets.

Main physicochemical properties: round tablets with white-gray to pale brown specks. With a bevel, a score and embossing of "500" and "mg" on both sides of the score on one side of the tablet, and "PENTASA" on the other side of the tablet. Diameter: 13.5 mm.

Pharmacotherapeutic group

Anti-inflammatory drugs used in intestinal diseases. Aminosalicylic acid and similar drugs.

ATX code A07E C02.

Pharmacological properties

Pharmacodynamics.

Mesalazine is the active ingredient in sulfasalazine, which is used to treat ulcerative colitis and Crohn's disease.

Clinical studies suggest that the therapeutic properties of mesalazine when administered orally and rectally are due to its local action on inflamed areas of the intestine rather than a systemic effect. Available information indicates that the severity of intestinal inflammation in patients with ulcerative colitis is inversely correlated with the concentration of mesalazine in the mucosa.

Patients with inflammatory bowel disease exhibit increased leukocyte migration, abnormal cytokine production, increased production of arachidonic acid metabolites (especially leukotrienes B4), and increased concentrations of free radicals in inflamed intestinal tissues.

The mechanism of action of mesalazine is not fully understood, although mechanisms such as stimulation of the γ-form of peroxisome proliferator-activated receptors (PPAR-γ) and inhibition of nuclear factor kappa-B (NF-κB) in the intestinal mucosa may be involved.

The pharmacological effects of mesalazine in in vitro and in vivo studies are to inhibit leukocyte chemotaxis, reduce cytokine and leukotriene production, and neutralize free radicals. Although this has not been definitively established, in any case, the above processes play a major role in the clinical efficacy of mesalazine.

The risk of colorectal cancer is slightly increased in ulcerative colitis. A comparative analysis of 9 non-experimental studies (3 cohort studies and 6 case-control studies) of 334 colorectal cancer cases and 140 dysplasia cases in 1932 patients with ulcerative colitis demonstrated that patients treated with mesalazine had a 50% reduced risk of colorectal cancer and showed a combined clinical outcome for colorectal cancer and dysplasia. The reduction in colorectal cancer risk is dose-dependent, as evidenced by a comparative analysis of daily dose records studies, according to which mesalazine has a chemopreventive effect at a dose of ≥ 1.2 g/day. In addition, chemoprophylaxis is related to the lifetime dose of mesalazine. Maintenance treatment with mesalazine has been shown to reduce the risk of colorectal cancer.

The effects of mesalazine, demonstrated in experimental models and patient biopsies, support a role for the drug in preventing colorectal cancer associated with ulcerative colitis and in downregulating inflammatory and non-inflammatory signaling pathways involved in the development of colorectal cancer associated with colitis. However, meta-analyses that included reference and general populations provided mixed clinical information regarding the benefit of mesalazine in reducing the risk of carcinogenesis associated with ulcerative colitis.

Pharmacokinetics.

The therapeutic effect of mesalazine is mainly determined by its local contact with the area of inflammation of the intestinal mucosa.

Pentasa, prolonged-release tablets, are mesalazine microgranules coated with ethylcellulose. After ingestion and dissolution, mesalazine is gradually released from each microgranule as the tablet passes through the gastrointestinal tract from the duodenum to the rectum at any pH of the intestinal environment. One hour after oral administration of the drug, the microgranules are found in the duodenum, regardless of food intake. The average intestinal transit time in healthy volunteers is 3–4 hours.

Absorption. From 30 to 50% of the orally administered drug in healthy volunteers is absorbed in the small intestine. Mesalazine is detected in the blood plasma as early as 15 minutes after administration, and the maximum concentration of mesalazine in the blood plasma is reached 1–6 hours after administration. The concentration of mesalazine in the blood plasma gradually decreases and is not detected 12 hours after administration. The plasma concentration curve of acetylmesalazine has the same character, but in general it is characterized by higher concentrations and slower elimination.

The once daily (1 x 4 g/day) and twice daily (2 x 2 g/day) dosing regimens of mesalazine result in comparable systemic exposure (AUC) over 24 hours and indicate a continuous release of mesalazine from the dosage form over the treatment period. With oral administration, steady state is reached after 5 days.

The molecular weight of mesalazine is 153.13 g/mol; acetylmesalazine is 195.17 g/mol.

The passage and release of mesalazine after oral administration are independent of food intake, while systemic exposure may be increased.

Distribution: Mesalazine is approximately 50% bound to plasma proteins and acetylmesalazine is approximately 80%. Mesalazine and acetylmesalazine do not cross the blood-brain barrier.

Biotransformation. Mesalazine is converted to N-acetylmesalazine (acetylmesalazine) both presystemically in the intestinal mucosa and systemically in the liver, mainly by N-acetyltransferase-1 (NAT-1). Minor acetylation is carried out by colonic bacteria. Acetylation of mesalazine is probably not related to the acetylation phenotype of the patient. The metabolic ratio in plasma of acetylmesalazine to mesalazine is 3.5 and 1.3, respectively, after oral administration of 500 mg 3 times a day and 2 g 3 times a day, reflecting a dose-dependent acetylation, which in turn may be due to saturation with the drug. Acetylmesalazine is also considered to be clinically and toxicologically inactive.

Elimination: The elimination half-life of mesalazine is approximately 40 minutes, of acetyl-mesalazine approximately 70 minutes. Due to the gradual release of mesalazine from the drug during passage through the gastrointestinal tract, the elimination half-life after oral administration cannot be determined. However, steady-state is achieved after oral administration for 5 days.

Mesalazine and acetylmesalazine are excreted in the urine and feces. Acetylmesalazine is mainly present in the urine.

In patients with impaired liver and kidney function, the risk of kidney damage may be increased due to a decrease in the rate of excretion and an increase in the systemic concentration of mesalazine.

Special patient groups

Pathophysiological changes such as diarrhoea and increased bowel activity, which are seen in active inflammatory bowel disease, have only a minor effect on the penetration of mesalazine into the intestinal mucosa after oral administration. In patients with accelerated intestinal transit, an increase of 20–25% of the daily dose was observed in the urine. Excretion in the faeces was similarly increased.

Indication

Mild to moderate nonspecific ulcerative colitis, Crohn's disease.

Contraindication

Hypersensitivity to mesalazine, to any of the components of the drug or to salicylates. Severe liver and/or kidney dysfunction. Gastric or duodenal ulcer. Hemorrhagic diathesis.

Interaction with other medicinal products and other types of interactions

Concomitant treatment with Pentasa and azathioprine, 6-mercaptopurine or thioguanine in studies has resulted in an increased incidence of myelosuppressive effects; an interaction between these agents is likely. The mechanism of this interaction is not fully understood. It is recommended to regularly monitor leukocyte levels and adjust the doses of thiopurines accordingly.

According to unconfirmed data, mesalazine may weaken the anticoagulant effect of warfarin.

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

Application features

Most patients with intolerance or hypersensitivity to sulfasalazine can use Pentasa without the risk of such reactions. However, the drug should be used with caution in patients with an allergy to sulfasalazine (risk of allergy to salicylates).

In case of acute symptoms of intolerance, such as cramps and acute abdominal pain, fever, severe headache and rash, treatment should be discontinued immediately.

The drug should be used with caution in patients with impaired liver function.

Before starting or during treatment, at the discretion of the physician, liver function tests such as ALT or AST should be monitored.

The drug is not recommended for use in patients with renal insufficiency. Renal function should be monitored regularly (e.g. serum urea, serum creatinine, urine sedimentation rate and methaemoglobin concentration), especially at the beginning of treatment. The patient's urological status (test strips) should be determined before and during treatment, at the discretion of the physician. In patients who develop impaired renal function during treatment, mesalazine-induced nephrotoxicity should be suspected.

Nephrolithiasis, including the formation of stones consisting of 100% mesalazine, has been reported with the use of mesalazine. Patients should be advised to drink sufficient fluids during treatment.

Patients with impaired respiratory function, in particular bronchial asthma, should be under close medical supervision during the course of treatment (see section "Adverse reactions").

Mesalazine-induced hypersensitivity reactions of the heart (myocarditis and pericarditis) occur rarely. Pathological changes in the blood system have been observed very rarely against the background of taking mesalazine. Before starting and during treatment, the doctor may recommend, at his discretion, a blood test with a leukocyte formula.

Concomitant treatment with azathioprine, 6-mercaptopurine or thioguanine may increase the risk of haematological abnormalities (see section 4.5). If signs or suspicion of such adverse reactions occur, treatment should be discontinued.

It is recommended that additional blood and urine tests be performed 14 days after the start of treatment, and then 2–3 additional tests at 4-week intervals. If the results are within normal limits, subsequent tests should be performed every three months. If additional symptoms occur, these tests should be performed immediately.

Interference with laboratory tests

There have been several reports of possible interference with the determination of urinary normetanephrine by liquid chromatography, resulting in false-positive results in patients exposed to sulfasalazine or its metabolite, mesalamine/mesalazine.

Severe skin adverse reactions

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

The use of mesalazine should be discontinued at the first appearance of severe skin reactions such as skin rash, damage to the intestinal mucosa or any other signs of hypersensitivity.

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

Use during pregnancy or breastfeeding

Pregnancy.

Mesalazine is known to cross the placental barrier. The concentration of the drug in cord blood plasma is lower than that in maternal plasma. The same concentrations of the metabolite acetylmesalazine are found in cord and maternal plasma.

Several non-experimental studies have not shown any teratogenic effects and no evidence of significant risk to humans. Animal studies of oral mesalazine do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal and foetal development, parturition or postnatal development.

There are no adequate and well-controlled studies of Pentasa in pregnant women. Limited published data on mesalazine suggest no increased overall rate of birth defects.

Some evidence suggests an increased risk of preterm birth, stillbirth, and low birth weight, but these adverse pregnancy outcomes may also be associated with active inflammatory bowel disease.

There have been reports of blood disorders (pancytopenia, leukopenia, thrombocytopenia, anemia) in newborns whose mothers used mesalazine.

Only one case of neonatal renal failure has been reported following prolonged use of high-dose mesalazine (2–4 g orally) during pregnancy.

During pregnancy, mesalazine should only be used if, in the opinion of the doctor, the potential benefit to the mother outweighs the potential risk to the fetus. The disease itself (inflammatory bowel disease) may increase the risk of adverse pregnancy outcomes.

Breast-feeding.

Mesalazine passes into breast milk. The concentration of mesalazine in breast milk is lower than in the mother's blood, while the metabolite formed (acetylmesalazine) appears in milk in the same or higher concentrations.

Data on oral use during breastfeeding are limited. Controlled studies of Pentasa during breastfeeding have not been conducted. Hypersensitivity reactions, such as diarrhea, in infants cannot be excluded. If diarrhea occurs in an infant, breastfeeding should be discontinued.

Pentasa can be taken during breastfeeding, but only if, in the opinion of the doctor, the potential benefit to the mother outweighs the potential risk to the child.

Fertility.

Animal studies have shown no effect of mesalazine on male and female fertility.

Ability to influence reaction speed when driving vehicles or other mechanisms

Mesalazine has no or negligible influence on the ability to drive or use machines. If dizziness occurs during treatment with the drug, you should refrain from driving.

Method of administration and doses

As a rule, children weighing less than 40 kg are given half the adult dose, and children weighing more than 40 kg are given the full adult dose.

The tablets should be taken orally, without chewing. To make swallowing easier, the tablet can be dissolved in 50 ml of cold water. Stir and drink immediately.

The duration of treatment is determined by the doctor depending on the course of the disease.

Children.

The drug should not be used to treat children under 6 years of age.

Overdose

There is only limited clinical experience with overdose of Pentasa, which does not indicate renal or hepatic toxicity. There is no specific antidote, treatment should be symptomatic and supportive. There have been reports of patients taking daily doses of up to 8 g for a month without any adverse effects.

Due to the development of prolonged-release granules and the specific pharmacokinetic properties of mesalazine, poisoning is not expected even when taking the drug in large doses.

In general, the symptoms should correspond to those of poisoning with salicylic acid salts: acid-base intoxication, hyperventilation and pulmonary edema, dehydration caused by sweating and vomiting, hypoglycemia.

Overdose treatment: in case of acidosis or alkalosis - restoration of acid-base and electrolyte balance; in case of dehydration - rehydration; in case of hypoglycemia - use of glucose. Additionally, intravenous infusion of electrolyte solutions should be carried out to increase diuresis. Careful monitoring of renal function.

Side effects

The most common adverse reactions observed in clinical trials are diarrhea, nausea, abdominal pain, headache, vomiting, and rash. Hypersensitivity reactions and drug fever have occasionally been reported.

Severe cutaneous adverse reactions (SCARs), including drug-induced eosinophilia with systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in association with mesalazine treatment (see section 4.4).

The frequency of adverse reactions reported during clinical trials and during post-marketing surveillance is defined as follows: common (≥ 1/100 to < 1/10), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency unknown (cannot be estimated from the available data).

Blood and lymphatic system disorders: very rare – eosinophilia (as part of an allergic reaction), anemia, aplastic anemia, leukopenia (including granulocytopenia and neutropenia), thrombocytopenia, agranulocytosis, pancytopenia.

Immune system disorders: very rare – pancolitis, hypersensitivity reactions including anaphylactic reactions, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Nervous system: common - headache; rare - dizziness; very rare - peripheral neuropathy, benign intracranial hypertension (in children during puberty).

Cardiac disorders: rare – myocarditis* and pericarditis*.

Respiratory, thoracic and mediastinal disorders: very rare - allergic and fibrotic changes in the lungs (including dyspnea, cough, bronchospasm, allergic alveolitis, pulmonary eosinophilia, interstitial lung disease, pulmonary infiltration, pneumonitis).

Gastrointestinal: common – diarrhea, abdominal pain, nausea, vomiting, flatulence; rare – increased amylase levels, acute pancreatitis*; very rare – pancolitis.

Skin and subcutaneous tissue disorders: common - rash (including urticaria, erythematous rash); rare - photosensitivity reactions**; very rare - reversible alopecia, angioedema, allergic dermatitis, erythema multiforme; frequency unknown - Stevens-Johnson syndrome, toxic epidermal necrolysis, drug-induced eosinophilia with systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders: very rare – myalgia, arthralgia, lupus erythematosus-like reactions.

Renal and urinary disorders: very rare - renal dysfunction (including acute and chronic interstitial nephritis*, nephrotic syndrome, renal failure (acute and chronic), which may disappear upon discontinuation of the drug); frequency unknown - nephrolithiasis***, urine discoloration***.

From the reproductive system and mammary glands: very rare - oligospermia (reversible).

General disorders: very rare – drug fever.

*The mechanism of development of mesalazine-induced myo- and pericarditis, pancreatitis, nephritis and hepatitis is unknown, but its allergic origin is possible.

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

***See the “Application Features” section for detailed information.

It is important to note that some of these disorders may be associated with inflammatory bowel disease.

Adverse reaction reporting

Reporting of suspected adverse reactions after the approval of a medicinal product is important. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Expiration date

3 years.

Storage conditions

Keep out of the reach of children. Store at a temperature not exceeding 25 °C in a place protected from light.

Packaging

10 tablets in a blister, 5 or 10 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

Ferring GmbH, Germany.

Location of the manufacturer and address of its place of business.

Wittland 11, 24109 Kiel, Germany.