Pentasa prolonged-release granules 2 g sachet No. 60

Instructions for Pentasa prolonged-release granules 2 g sachet No. 60

Composition

active ingredient: mesalazine;

1 sachet contains 1 g or 2 g of mesalazine;

excipients: povidone, ethylcellulose.

Dosage form

Extended-release granules.

Main physicochemical properties: cylindrical granules from white-gray to light white-brown in color.

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 indicate that the therapeutic properties of mesalazine when administered orally and rectally are due more to its local action on inflamed areas of the intestine than to its systemic effect.

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

The pharmacological effect of mesalazine in in vitro and in vivo studies is to inhibit leukocyte chemotaxis, reduce the production of cytokines and leukotrienes, and neutralize free radicals. The mechanism of action of mesalazine has not been determined.

A comparative analysis of 9 non-experimental studies (3 cohort studies and 6 case-control studies) of 334 cases of colorectal cancer and 140 cases of dysplasia among 1932 patients with ulcerative colitis demonstrated that patients treated with mesalazine had a 50% reduction in the risk of colorectal cancer and a combined clinical outcome for colorectal cancer and dysplasia. The reduction in the risk of colorectal cancer was dose-dependent, as demonstrated by a comparative analysis of daily dose records studies, according to which mesalazine ≥ 1.2 g/day has a chemopreventive effect. In addition, chemoprevention is associated with continuous mesalazine administration. Finally, 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 caused by ulcerative colitis, as well as in reducing the number of inflammatory and non-inflammatory signaling pathways involved in the development of colorectal cancer caused by colitis.

Pharmacokinetics

Mesalazine granules are coated with ethylcellulose. After application and dissolution, mesalazine is gradually released from each microgranule during the passage of the tablet 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.

Biotransformation. Mesalazine is converted to N-acetyl-mesalazine (acetyl-mesalazine) both presystemically in the intestinal mucosa and systemically in the liver. Minor acetylation occurs with the participation of colonic bacteria, resulting in the formation of N-acetyl-5-aminosalicylic acid. Acetylation of mesalazine is apparently not associated with individual patient phenotype. Acetyl-mesalazine is also considered to be clinically and toxicologically inactive.

Absorption. From 30 to 50% of the drug is absorbed in the small intestine after oral administration. Mesalazine is detected in the blood plasma as early as 15 minutes after administration. The maximum concentration of mesalazine in the blood plasma is noted 1-4 hours after administration of the drug. The concentration of mesalazine in the plasma gradually decreases and is not detected 12 hours after administration. The plasma concentration curve of acetyl-mesalazine has the same character, but in general it is characterized by higher concentrations and slower elimination. The metabolic ratio in plasma of acetyl-mesalazine to mesalazine is from 3.5 to 1.3 after oral administration of 500 mg 3 times a day and 2 g 3 times a day, respectively, which reflects saturated dose-dependent acetylation.

The mean steady-state plasma concentrations of mesalazine are 2 μmol/l, 8 μmol/l and 12 μmol/l after 1.5, 4 and 6 g daily, respectively. For acetyl-mesalazine, these concentrations are 6 μmol/l, 13 μmol/l and 16 μmol/l, respectively. The passage and release of mesalazine after oral administration are independent of food intake, as systemic absorption will be reduced.

Elimination: The plasma half-life of mesalazine is approximately 40 minutes and that of acetyl-mesalazine is approximately 70 minutes. Since mesalazine is continuously released during gastrointestinal transit, it is not possible to determine the half-life after oral administration. Studies have shown that mesalazine reaches steady-state concentrations after oral administration within 5 days.

Mesalazine and acetyl-mesalazine are excreted in the urine and feces; acetyl-mesalazine is excreted primarily in the urine.

Indication

Ulcerative colitis.

Crohn's disease.

Contraindication

Hypersensitivity to mesalazine, to any of the components of the drug or to salicylates, gastric and duodenal ulcer in the acute stage, severe hepatic and/or renal failure, hemorrhagic diathesis.

Interaction with other medicinal products and other types of interactions

During complex treatment with Pentasa and azathioprine, 6-mercaptopurine or thioguanine, some studies have shown a higher frequency of myelosuppressive effects, which supposedly indicates the presence of an interaction, but the mechanism of interaction is not fully established. Regular monitoring of leukocyte levels is recommended, and the dosage regimen of thiopurines should be adjusted.

The evidence that mesalazine can reduce the anticoagulant effect of warfarin is weak.

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

Pentasa (5-aminosalicylic acid) can be administered with caution to most patients who have had allergic reactions to sulfasalazine or are at risk of developing allergy to salicylates; careful observation should be maintained when treating such patients.

In case of acute symptoms: cramps, abdominal pain, fever, uncontrollable headache or rash, treatment should be stopped immediately.

The drug should be used with caution in patients with mild to moderate renal or hepatic impairment. Liver function tests (ALT and AST) should be monitored before and during treatment. Renal function should be monitored regularly, particularly by measuring serum creatinine (especially in the initial phase of treatment). Before and during treatment, urine should be checked (using a dipstick) at the discretion of the physician. Impaired renal function in patients during treatment may be due to the nephrotoxic effects of mesalazine. Concomitant use of known nephrotoxic agents, such as nonsteroidal anti-inflammatory drugs and azathioprine, may increase the risk of adverse renal reactions.

Patients with impaired respiratory function, especially asthma, should be under the supervision of a physician throughout the entire course of treatment.

If myocarditis or pericarditis is suspected or if there is a change in the blood composition, treatment should be stopped immediately. Before starting and during treatment, the doctor may recommend a blood test at his discretion.

It is recommended to perform tests before starting treatment, after 2 weeks, and then 2–3 times with an interval of 4 weeks. If the test results are within normal limits, periodic tests can be performed every three months or when symptoms of damage appear.

Concomitant use of mesalazine with azathioprine or 6-mercaptopurine increases the risk of changes in blood composition. If such reactions are suspected, treatment should be discontinued.

Elderly patients do not need to reduce the dosage.

Use during pregnancy or breastfeeding

Mesalazine is known to cross the placental barrier. The concentration of the drug in the umbilical cord plasma is approximately one-tenth of the concentration in maternal plasma. The same concentrations of the metabolite acetyl-mesalazine are found in umbilical cord and maternal plasma. Experimental studies on animals have not revealed any teratogenic or mutagenic effects. Limited data on the use of this substance by pregnant women do not allow an assessment of possible toxic effects.

Pentasa is not recommended for use during pregnancy, except in cases of urgent need.

There have been reports of haematological disorders (pancytopenia, leukopenia, thrombocytopenia, anaemia) in neonates whose mothers had taken mesalazine. Only one case of renal failure in a neonate was reported after prolonged use of high doses of mesalazine (2-4 g orally) during pregnancy.

Data on oral administration 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 develops 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.

The ability to influence the reaction speed when driving or working with other mechanisms

In case of side effects from the nervous system (dizziness), you should refrain from driving or operating other mechanisms.

Method of administration and doses

In general, it is recommended that children weighing up to 40 kg take half the adult dose and children weighing over 40 kg take the usual adult dose.

Other treatment should be considered for patients with Crohn's disease who have not responded to a daily dose of up to 4 g mesalazine for 6 weeks and for patients with Crohn's disease who have a flare-up despite maintenance therapy of 4 g mesalazine per day.

The contents of the sachet should be poured into the mouth and washed down with water. Do not chew.

It is important to take the drug regularly to achieve optimal effect.

Children

It is contraindicated for use in children under 6 years of age.

Overdose

Given the unique dosage form in the form of prolonged-release granules and the specific pharmacokinetic properties of mesalazine, only a small part of the active substance has a systemic effect, therefore, the development of overdose symptoms should not be expected even with high doses of the drug.

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

Treatment is symptomatic: restoration of acid-base balance depending on the situation and replacement of electrolyte losses in mixed alkalosis/acidosis; replenishment of fluid volume lost due to excessive sweating and vomiting; in case of hypoglycemia - administration of glucose. In addition, gastric irrigation and intravenous electrolyte transfusion to increase diuresis. Careful monitoring of renal function.

Adverse reactions

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.

The following adverse reactions may develop: stomatitis, proteinuria, hematuria, itching, dermatoses, weakness, mumps, decreased tear production.

The frequency of adverse reactions reported during clinical trials and post-marketing surveillance is defined as follows:

common (≥ 1% to <10%), uncommon (≥ 0.1% to <1%), rare (≥ 0.01% to <0.1%), very rare (<0.01%).

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, isolated cases – hypersensitivity reactions.

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

Cardiac disorders: rare – myocarditis* and pericarditis*.

Gastrointestinal disorders: common – diarrhea, abdominal pain, nausea, vomiting, rare – increased amylase levels (in blood and/or urine), acute pancreatitis*, flatulence, very rare – exacerbation of colitis symptoms.

Hepatobiliary disorders: very rare - increased levels of liver enzymes, cholestasis and bilirubin parameters, hepatotoxicity (including hepatitis*, cholestatic hepatitis, cirrhosis, hepatic failure).

Skin and subcutaneous tissue disorders: common - rash (including urticaria, erythematous rash), rare - photosensitivity reactions, very rare - alopecia, angioedema.

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

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

Genital disorders: very rare – oligospermia (reversible).

General disorders: isolated cases of drug fever.

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

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

Expiration date

2 years.

Storage conditions

Keep out of reach of children. Store in original packaging at a temperature not exceeding 25 °C.

Packaging

50, 100 or 150 sachets of 1 g granules in a cardboard box.

60 sachets of 2 g granules in a cardboard box.

Vacation category

According to the recipe.

Producer

Responsible for the release of the series:

Ferring GmbH, Germany.

Location of the manufacturer and address of its place of business

Wittland 11, Postfach 21 45, D-24109 Kiel, Germany.