Mezavant, 1,2g 60 pcs.

Pharmacotherapeutic group: Inflammatory bowel medicine.

ATX code: A07EC02

Pharmacological properties Pharmacodynamics

em>Mechanism of action

Mesalazine is a 5-aminosalicylic acid derivative. The mechanism of action of mesalazine is not fully understood, but the drug has been found to have a local anti-inflammatory effect on intestinal epithelial cells. In patients with chronic inflammatory bowel disease, synthesis of arachidonic acid metabolites by cyclooxygenase and lipoxygenase pathways is increased in the mucosa. It is possible that mesalazine attenuates inflammation by inhibiting cyclooxygenase and inhibiting prostaglandin synthesis in the colon. Mesalazine has the ability to inhibit the activation of nuclear factor kappa-B, NFkB, and hence the production of key proinflammatory cytokines. Recently, it has been suggested that a deficiency of nuclear PPAR-γ receptors (the γ form of receptors activated by peroxisome proliferator-activated receptors) may be associated with the development of ulcerative colitis. PPAR-γ receptor agonists have been shown to be effective in ulcerative colitis. Accumulating evidence suggests that the effect of mesalazine may be realized by acting on PPAR-γ receptors.

Pharmacokinetics

The tablet of the drug Mesavant has a core containing 1.2 g of mesalazine in a multimatrix system. The core is surrounded by a shell of a copolymer of methacrylic acid and methyl methacrylate taken in ratios (1:1) to (1:2); the composition of the shell is chosen so that the release of mesalazine begins only when the pH reaches about 7.

The mechanism of action of mesalazine is not fully understood, but mesalazine (5-ASC) is thought to have local action, so the clinical effect of the drug does not correlate with the pharmacokinetic characteristics of the substance. The main route of excretion of mesalazine is metabolism to N-acetyl-5-aminosalicylic acid, which is pharmacologically inactive.

absorption

The studies with gamma scintigraphy showed that, after a single dose of 1.2 g on an empty stomach in healthy volunteers, mesalazine passes rapidly and unchanged through the upper gastrointestinal tract. This reveals traces of radioactive isotope-labeled indicator throughout the colon, indicating that mesalazine enters these parts of the gastrointestinal tract. Complete disintegration of the Mesavant tablet and release of mesalazine was observed after approximately 17.4 hours.

After administration to healthy volunteers at a dose of 2.4 g or 4.8 g once daily for 14 days, absorption of mesalazine was 21 to 22% of the dose taken.

After a single dose in healthy volunteers on an empty stomach at doses of 1.2 g, 2.4 g and 4.8 g, the plasma concentration of mesalazine was determined 2 hours (median) after administration and reached the maximum value after 9 – 12 hours (median). Pharmacokinetic parameters were characterized by wide variability between patients. The level of systemic exposure (AUC, area under the concentration-time curve) for mesalazine at doses ranging from 1.2 g to 4.8 g of mesalazine was proportional to the dose taken. The maximum plasma concentration (C_max) of mesalazine in the dose range of 1.2 g to 2.4 g increased approximately in direct proportion, whereas in the dose range of 2.4 g to 4.8 g mesalazine increased in proportion to the dose but to a lesser extent, with a normalized dose at 4.8 g averaging 74% of a dose equal to 2.4 g, based on geometric mean values. In a pharmacological study of single and multiple doses of 2.4 g and 4.8 g of mesalazine with common food, mesalazine was detectable in plasma after 4 hours, with maximum concentration reached 8 hours after a single dose. At equilibrium (which was usually reached after 2 days of administration), 5-ASC accumulation was 1.1 and 1.4 times higher for doses of 2.4 g and 4.8 g, respectively, than for a single dose.

Single-dose administration of mesalazine at a dose of 4.8 g with fatty foods was accompanied by a delayed phase of absorption. Under these conditions, mesalazine was detectable in plasma approximately 4 hours after ingestion. However, fat-rich foods increased the systemic exposure of mesalazine (mean C_max by 91%, mean AUC by 16%) compared with fasting food.

In a pharmacokinetic study of mesalazine, healthy volunteers of both sexes (n=71, 28 young (18 to 35 years), 28 elderly (65 to 75 years), and 15 older than 75 years) took mesalazine at a single dose of 4.8 g on an empty stomach. Increased age was accompanied by increased systemic exposure of mesalazine and its metabolite N- acetyl-5-aminosalicylic acid (calculated based on AUC_0-t AUC0_-∞ and C_max) approximately doubled, but had no effect on the proportion of mesalazine absorbed. Increased age was accompanied by a delay in the apparent half-life of mesalazine, although variability between patients was pronounced. Systemic exposure in selected subjects was inversely correlated with renal function as assessed by estimated creatinine clearance.

Distribution

Mesalazine is thought to have a similar distribution profile to other mesalazine-containing drugs. Mesalazine has a relatively low volume of distribution of approximately 18 liters, indicating minimal systemic distribution. At in vitro plasma concentrations of mesalazine up to 2.5 µg/mL and concentrations of N-acetyl 5-aminosalicylate up to 10 µg/mL, binding to plasma proteins was 43% and 78-83%, respectively.

Metabolism

The only major metabolite of mesalazine is the pharmacologically inactive N-acetyl 5-aminosalicylic acid. It is formed under the action of N-acetyltransferase-1 in the cells of the liver and cytosol cells of the intestinal mucosa.

Evolution

Absorbed mesalazine is excreted mainly by the kidneys after acetylation to N- acetyl-5-aminosalicylic acid. However, a small amount of the drug is excreted by the kidneys and unchanged. Less than 8% of the absorbed dose of mesalazine (21-22% of the administered dose is absorbed) is excreted unchanged in the urine within 24 hours, while more than 13% is excreted as N-acetyl-5-aminosalicylic acid. The apparent terminal elimination half-life of mesalazine and its major metabolite after doses of 2.4 g and 4.8 g were, on average, 7-9 and 8-12 hours, respectively.

In adults, mean renal clearance (CLR) was 1.8 l/h and 2.9 l/h at single doses of 2.4 g and 4.8 g, respectively, and slightly higher on day 14 of multiple dosing: 5.5 l/h and 6.4 l/h at doses of 2.4 g/day and 4.8 g/day. Mean renal clearance of the metabolite was higher, being approximately 12-15 l/h after single and multiple doses of mesalazine at doses of 2.4 g/d and 4.8 g/d.In pediatric patients, mean renal clearance of 5-ASA at equilibrium ranged from approximately 5.0 to 6.5 l/h (83-108 ml/min), similar to that observed in adult subjects. There was a tendency for CLR to decrease with increasing dose, and individual CLR estimates varied widely. The mean CLR of N-acetyl-5-aminosalicylic acid ranged from 10.0 to 16.2 L/h (166-270 mL/min) with a tendency to decrease with increasing dose.

Special patient groups

Patients with hepatic impairment

There are no data on the use of mesalazine in patients with hepatic impairment. After a single dose of 4.8 g of mesalazine, systemic exposure of mesalazine in elderly patients (older than 65 years, with an average creatinine clearance of 68-76 ml/min) was superior to that in younger patients (18-35 years old, with an average creatinine clearance of 124 ml/min) by up to 2 times.

Patients with renal impairment

The systemic exposure in an individual analysis was inversely correlated with renal function as assessed by creatinine clearance.

Elderly patients

Pharmacokinetics data in the elderly have not been investigated.

Potential effects on the safe use of mesalazine in clinical practice in elderly patients should be considered. In addition, in patients with impaired renal function, the associated decreased excretion rate and increased systemic concentration of mesalazine may pose an increased risk of nephrotoxic adverse reactions (see section “Cautions”).

Gender

In various clinical studies of mesalazine, the AUC value of mesalazine in plasma was found to be 2 times higher in women than in men.

Race

Based on limited pharmacokinetic data, the pharmacokinetics of 5-ASA and N-acetyl-5-aminosalicylic acid appear to be comparable in subjects of European and Hispanic origin.

Indications

Active ingredient

Composition

1 tablet contains:

Active ingredient: mesalazine 1200.0 mg.

Associates: sodium carmellose (7MF) 11.3 mg, sodium carmellose (7HXF) 38.7 mg, carnauba wax 5.0 mg, stearic acid 10.0 mg, colloidal silica 2.0 mg, sodium carboxymethyl starch (type A) 30.0 mg, talc 11.0 mg, magnesium stearate 14.0 mg.

Pill coating: talk 17.8 mg, methacrylic acid and methyl methacrylate copolymer [1:1] 16.0 mg, methacrylic acid and methyl methacrylate copolymer [1:2] 16.0 mg, triethylcitrate 3.2 mg, titanium dioxide 6.0 mg, iron oxide red dye 3.0 mg, macrogol 6000 1.0 mg.

How to take, the dosage

Interaction

Special Instructions

Serious skin adverse reactions

The occurrence of severe skin adverse reactions (SARA), including Stevens-Johnson syndrome (SSD) and toxic epidermal necrolysis (TEN), has been reported in connection with treatment with mesalazine. Mesalazine should be discontinued at the first appearance of signs and symptoms of severe skin reactions, such as skin rash, mucosal lesions, or any other signs of hypersensitivity.

Renal or hepatic impairment

In cases of renal dysfunction, including the development of nephropathy with minimal changes, acute/chronic interstitial nephritis and renal failure have been described when using drugs containing mesalazine or which are prodrugs of mesalazine. Caution should be exercised when taking the drug in patients with established mild to moderate renal dysfunction. All patients are advised to undergo renal function tests before starting treatment and then repeat them at least 2 times per year during treatment.

Lung function impairment

Patients with chronic lung function impairment, especially asthma, are at risk for hypersensitivity reactions and should be closely monitored.

Pathological changes in blood composition (blood dyscrasia)

Blood dyscrasia has rarely been observed after treatment with mesalazine. If a patient develops unexplained bleeding, bruising, purpura, anemia, fever, or sore throat, a hematologic examination should be performed. If blood dyscrasia is suspected, treatment should be stopped.

Hypersensitivity reactions in the heart

Rare cases of hypersensitivity reactions in the heart (myocarditis and pericarditis) have been described with the use of Mesavant or other drugs containing mesalazine. Caution should be exercised when prescribing this drug in patients with diseases predisposing to the development of myocarditis or pericarditis. If such a hypersensitivity reaction is suspected, medications containing mesalazine should not be reapplied.

Acute intolerance syndrome

The use of mesalazine is associated with the development of acute intolerance syndrome, which in some cases is difficult to distinguish from exacerbation of inflammatory bowel disease. Although the incidence of this phenomenon has not been precisely established, in controlled clinical trials of mesalazine or sulfasalazine it was 3%. Symptoms include abdominal cramps, acute abdominal pain, diarrhea with an admixture of blood, sometimes fever, headache, and rash. If acute intolerance syndrome is suspected, the drug containing mesalazine should be stopped immediately and not restarted.

Hepatic dysfunction

Hepatic enzyme elevations have been reported in patients taking medications containing mesalazine. Caution is advised in patients with impaired liver function.

Allergy to sulfasalazine

Patients with sulfasalazine allergy should be treated with caution due to the potential risk of cross-sensitivity reactions between sulfasalazine and mesalazine.

Upper gastrointestinal tract obstruction

Organic or functional upper gastrointestinal tract obstruction may delay the development of the drug effect.

Sodium content

The drug contains less than 1 mmol of sodium (23 mg) in the maximum recommended dose (4 tablets), which can be interpreted as “sodium-free.”

Nephrolithiasis

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

Interaction with laboratory test results

The use of mesalazine may lead to false test results showing increased levels of normetanephrine in the urine. Such results are possible when liquid chromatography with electrochemical detection is used because of the similarity between the chromatograms of normetanephrine and the main metabolite of mesalazine, N-acetyl-5-amino-salicylic acid (N-Ac-5-ACA). Therefore, an alternative selective method should be used to determine normetanephrine in urine.

Influence on the ability to drive vehicles, mechanisms

There have been no studies of the effect of mesalazine on the ability to drive vehicles and moving mechanisms. Mesalazine is not believed to affect this ability. However, patients should be warned about the possibility of dizziness and somnolence during the use of the drug. In case of the occurrence of the described adverse events, it is necessary to refrain from performing the specified activities.

Synopsis

Contraindications

Side effects

The most common adverse reactions (ARs) reported in clinical trials of Mesavant in 3,611 patients were colitis (including ulcerative colitis, 5.8%), abdominal pain (4.9%), headache (4.5%), changes in liver function tests (2.1%), diarrhea (2.0%) and nausea (1.9%).

The safety profile in the pediatric patient population is consistent with the safety profile in adult studies and post-registration use. The adverse reactions listed below are categorized according to organ and organ system involvement (MEDDRA) and frequency: very common (≥1/10); common (≥1/100 to < 1/10); infrequent (≥1/1,000 to < 1/100); rare (≥1/10,000 to < 1/1,000); frequency unknown (frequency cannot be estimated from available data).

not infrequently: *thrombocytopenia

frequently: *agranulocytosis

frequency unknown: *aplastic anemia, *leukopenia, *neutropenia, *pancytopenia

infrequent: facial edema

frequency unknown: *hypersensitivity, anaphylactic shock, angioneurotic edema, Stevens-Johnson syndrome (SJS), drug rash accompanied by eosinophilia and systemic manifestations (DRESS), toxic epidermal necrolysis (TEN)

/p> Nervous system disorders

often: *headache

infrequent: dizziness, drowsiness, tremor

frequency unknown: increased intracranial pressure, neuropathy

infrequent: ear pain Cardiac disorders infrequent: tachycardia

frequency unknown: *myocarditis, *pericarditis

often: hypertension

not infrequently: hypotension

infrequent: *pharyngolaryngeal pain

frequency unknown: Hypersensitivity pneumonitis (including interstitial pneumonitis, allergic alveolitis, eosinophilic pneumonitis), bronchospasm, pleurisy Gastrointestinal tract disorders

frequently: abdominal bloating, *abdominal pain, colitis, *diarrhea, dyspepsia, vomiting, flatulence, nausea

infrequent: pancreatitis, rectal polyp

often: *changes in liver function test values (e.g., alanine aminotransferase, aspartate aminotransferase, bilirubin)

frequency unknown: Hepatitis, hepatotoxicity, cholelithiasis

frequent: cutaneous itching, *cutaneous rash infrequent: acne, alopecia, urticaria seldom: photosensitization

often: arthralgia, back pain

infrequent: Myalgia

frequency unknown: SLE syndrome, lupus-like syndrome

frequently: *renal failure

frequency unknown: *interstitial nephritis, *nephrotic syndrome,

*nephrolithiasis

frequency unknown: Oligospermia (reversible)

often: asthenia, weakness, increased body temperature*

*See. “Special Indications”

Elevated intracranial pressure

Cases of increased intracranial pressure with optic disc edema (idiopathic intracranial hypertension or benign intracranial hypertension) have been reported with the use of mesalazine. If not diagnosed in time, this condition can lead to a narrowing of the visual fields and permanent loss of vision. If possible, mesalazine should be discontinued if this syndrome develops.

Photosensitization

Harsher reactions have been reported in patients with pre-existing skin conditions such as atopic dermatitis and atopic eczema.

Overdose

Pregnancy use

Similarities