Mezavant - instructions for use, dose, side effects, contraindications

Composition:1 tablet contains:
Active ingredient: mesalazine 1200 mg.
Excipients:
Core tablet: sodium carmellose (7MF) 11.3 mg, carmellose sodium (7HXF) 38.7 mg, carnauba wax 5.0 mg, stearic acid 10.0 mg, silicon dioxide colloid 2.0 mg, sodium carboxymethyl starch type A) - 30.0 mg, talc - 11.0 mg, magnesium stearate - 14.0 mg.
Tablet casing: talc - 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, triethyl citrate 3.2 mg, titanium dioxide 6 , 0 mg, iron dye red oxide - 3.0 mg, macrogol 6000 - 1.0 mg.

Description:Oblong biconvex tablets, covered with a shell of red-brown color. On one side - engraving "8476". On the cross section, the core of the tablet is from white to almost white.

Pharmacotherapeutic group:Antimicrobial and anti-inflammatory intestinal.

ATX: & nbsp

A.07.E.C.02 Mesalazine

A.07.E.C Aminosalicylic acid and its analogues

Pharmacodynamics:Mechanism of action
Mesalazine is a derivative of 5-aminosalicylic acid. The mechanism of action of mesalazine to the end has not been studied, but it has been found that the drug has a local anti-inflammatory effect on the intestinal epithelium. In patients with chronic inflammatory bowel disease in the mucosa, the synthesis of arachidonic acid metabolites by cyclooxygenase and lipoxygenase pathways is enhanced. Maybe, mesalazine reduces inflammation by inhibiting cyclooxygenase and inhibiting the synthesis of prostaglandins in the large intestine. Mesalazine has the ability to inhibit the activation of the nuclear factor kappa-B-NFkB and, consequently, the production of key pro-inflammatory cytokines. Recently, it has been suggested that deficiency of nuclear receptors PPAR-γ (γ-form of receptors activated by peroxisome proliferator) may be associated with the development of ulcerative colitis. The efficacy of PPAR-γ receptor agonists in ulcerative colitis was demonstrated. Accumulated evidence indicates that the effect of mesalazine can be realized by affecting the receptors of PPAR-γ.

Pharmacokinetics:The Mevangant tablet has a nucleus containing mesalazine (5-aminosalicylic acid, 5-ASA) in a multicomponent matrix. The core is surrounded by a shell of copolymers of methacrylic acid of types A and B; The membrane is designed so that the release of mesalazine begins only when the pH is above 7.
The mechanism of action of mesalazine is not fully understood, but it is believed that mesalazine (5-ASA) has a local effect, so the clinical effect of the drug does not correlate with the pharmacokinetic characteristics of the substance. The main way of excretion of mesalazine is metabolism up to 1h1-acetyl-5-aminosalicylic acid, which is pharmacologically inactive.
Suction:
Studies with gamma scintigraphy showed that after a single dose of healthy volunteers drug on an empty stomach at a dose of 1.2 g mesalazine quickly and unchanged, passes through the upper sections of the gastrointestinal tract. In this case, traces of 14C-labeled mesalazine are detected throughout the colon, which indicates the arrival of mesalazine in these parts of the gastrointestinal tract. The complete disintegration of the Mezavant tablet and the release of mesalazine was observed after approximately 17.4 hours.
After a single dose of healthy volunteers at a dose of 2.4 g or 4.8 g for 14 days, the absorption of mesalazine was 21-22% of the dose.
After a single dose of healthy volunteers on an empty stomach at a dose of 1.2 g, 2.4 g and 4.8 g, the concentration of mesalazine in the plasma was determined after 2 hours (median) after administration and reached a maximum value after 9-12 hours (median). Pharmacokinetic parameters showed a wide variability. The level of system exposure of mesalazine - AUC (area under the curve "concentration - time") - when taking the drug in the range from 1.2 g to 4.8 g was proportional to the dose taken.The maximum concentration (Cmax) of mesalazine in plasma in the dose range from 1.2 g to 2.4 g increased approximately in direct proportion, whereas from 2.4 g to 4.8 g increased less than proportionally to the dose.
In the study of a single and multiple administration of the drug at a dose of 2.4 g and 4.8 g with normal food mesalazine was detected in the blood plasma after 4 hours, reaching the maximum concentration in 8 hours after a single dose.
A single dose of Mezavant in a dose of 4.8 g with fatty food was accompanied by a slowing down of the absorption phase. In these conditions mesalazine was detected in the blood plasma approximately 6 hours after administration. However, food rich in fats raised the systemic exposure of mesalazine (mean Stach - 91%, average AUC - 16%) compared with fasting rates.
Distribution:
It is believed that the drug Mesavant has a similar distribution profile, as other mesalazine-containing drugs. Mesalazine has a relatively small volume of distribution of about 18 liters, which indicates a minimal systemic distribution. At a mesalazine concentration in blood plasma to 2.5 μg / ml and concentration of M-acetyl-5-aminosalicylate to 10 μg / ml, the substances were associated with plasma proteins by 43% and 78-83%, respectively.
Metabolism:
The only important metabolite of mesalazine is the pharmacologically inactive N-acetyl-5-aminosalicylic acid. It is formed by the action of N-acetyltransferase-1 in the cells of the liver and cytosol cells of the intestinal mucosa.
Excretion:
Sucked mesalazine is excreted mainly by the kidneys after acetylation to N-acetyl-5-aminosalicylic acid. Nevertheless, the drug in small amounts is excreted by the kidneys and unchanged. Of 21 to 22% of the absorbed dose of the drug, less than 8% of mesalazine is excreted unchanged in the urine within 24 hours. About 13% is excreted within 4 hours as N-acetyl-5-aminosalicylic acid. The apparent half-life of mesalazine and its main metabolite after taking the drug at a dose of 2.4 and 4.8 g was an average of 7-9 and 8-13 hours, respectively.
Special categories of patients:
Data on the use of Mezavant in patients with impaired liver function. After a single dose of Mesavant in a dose of 4.8 g, the systemic exposure of mesalazine in elderly patients (over 65 years of age, the average creatinine clearance of 68-76 ml / min) was superior to that in younger patients (18-35 years, average creatinine clearance 124 ml / min) up to 2 times.The level of systemic exposure is inversely proportional to the function of the kidneys, estimated by the creatinine clearance. This should be taken into account in the treatment of elderly patients with Mezavant.
In patients with impaired renal function, a decrease in the rate of excretion and an increase in the concentration of mesalazine in the blood plasma may occur, which may be accompanied by an increased risk of unwanted adverse reactions from the urinary system.
In women, the area under the AUC ("concentration-time") curve of mesalazine was 2 times that of men.
Based on a limited amount of pharmacokinetic data, the pharmacokinetics of 5-ASA and N-acetyl-5-ASA in persons of the South European and Hispanic group are considered the same.

Indications:- Induction of remission by clinical and endoscopic parameters in patients with mild to moderate ulcerative colitis.
- Maintenance of remission in patients with ulcerative colitis.

Contraindications:- Hypersensitivity to salicylates (including mesalazine) or any auxiliary component of the preparation.
- Severe renal dysfunction (GFR <30 mL / min / 1.73 m² ).
- Severe dysfunction of the liver.
- Children under 18 years of age (due to lack of data on the safety and efficacy of the drug in this category of patients).

Carefully:- mild or moderate renal impairment.
- Chronic impairment of lung function (bronchial asthma).
- Diseases predisposing to the development of myo- or pericarditis.
- The drug is administered with caution to patients who are allergic to sulfasalazine, because of possible cross-sensitivity to mesalazine.

Pregnancy and lactation:Pregnancy
Limited data on the use of mesalazine during pregnancy do not indicate an increased risk of congenital malformations. Mesalazine penetrates the placental barrier, but the concentration of the substance in the fetal tissues is much lower than when applied in therapeutic doses in adults. Animal studies did not reveal the adverse effects of mesalazine on the course of pregnancy, embryo / fetal development, childbirth, and postnatal development of offspring. Mesalazine should be used during pregnancy only if the possible benefit to the mother exceeds the potential risk to the fetus.Care should be taken when administering high doses of the drug.
Lactation period
Mesalazine is excreted in breast milk in small amounts, and the metabolite N-acetyl-5-aminosalicylic acid - in a higher concentration. During lactation mesalazine Use with caution and only if the possible benefit to the mother exceeds the potential risk to the child. In infants, cases of sporadic diarrhea have been described.
Ability to conceive
The available data do not indicate a prolonged effect of mesalazine on the ability of men to conceive.

Dosing and Administration:Mezavant is intended for oral administration once a day during meals. Tablets can not be crushed or chewed and should be swallowed whole.
Adults, including the elderly (over 65)
Induction of remission: 2.4 - 4.8 g (2 - 4 tablets) 1 time per day. For patients not sensitive to the minimum dose, the recommended maximum daily dose is 4.8 g. When taking the maximum dose (4.8 g / day), the effect of treatment should be evaluated after 8 weeks.
Maintenance of remission: 2.4 g (2 tablets) 1 time per day.
Children and teenagers under 18:
Due to the lack of safety and efficacy data, Mezavant is not recommended for use in children younger than 18 years of age.
Special studies of the use of Mezavant in patients with impaired liver or kidney function were not performed.

Side effects:The most common adverse events in clinical trials were headache, abdominal pain, and nausea. For none of the undesirable side reactions, the frequency did not exceed 10%. When using Mezavant, other adverse reactions were observed less often.
Adverse drug reactions
Mesavorant, as well as undesirable reactions that occur when taking other mesalazine-containing drugs are systematized relative to each of the organ systems using the following classification of frequency:
Very often (≥ 1/10)
Often (≥1 / 100, <1/10)
Infrequently (≥1 / 1000, <1/100)
Rarely (≥1 / 10000, <1/1000)
Very rarely (<1/10000), including isolated cases
On the part of the blood and lymphatic system
Infrequently: thrombocytopenia
Rarely: agranulocytosis
The frequency is unknown: aplastic anemia, leukopenia, neutropenia, pancytopenia.
From the central nervous system:
Often: headache.
Infrequent: dizziness, drowsiness, tremor.
Frequency unknown: neuropathy
From the side of the cardiovascular system
Often: increased blood pressure.
Infrequent: tachycardia, hypotension.
The frequency is unknown: myocarditis, pericarditis.
From the respiratory system:
Infrequent: pain in throat / larynx.
Frequency unknown: bronchospasm
From the gastrointestinal tract
Often: bloating, abdominal pain, diarrhea, dyspepsia, vomiting, flatulence, nausea, deviation of indicators of functional hepatic samples (aspartate aminotransferase, alanine aminotransferase, bilirubin).
Infrequently: colitis, pancreatitis, polyp of the rectum.
The frequency is unknown: hepatitis, cholelithiasis.
From the skin and subcutaneous tissues
Often: itching, rash.
Infrequent: acne, alopecia.
From the immune system:
Infrequently: urticaria.
The frequency is unknown: pneumonitis, as a manifestation of hypersensitivity (including interstitial pneumonitis, allergic alveolitis, eosinophilic pneumonitis), angioedema, a syndrome similar to systemic lupus erythematosus, anaphylactic reaction, Stevens-Johnson syndrome, drug-induced skin reaction accompanied by eosinophilia and systemic manifestations (DRESS ).
From the osteomuscular system, connective and bone tissue:
Often: arthralgia, concomitant muscle pain, back pain.
Infrequently: myalgia.
From the genitourinary system:
Rarely: kidney failure
Frequency unknown: interstitial nephritis.
General state
Often: asthenia, fever.
Infrequent: swelling of the face, weakness.

Overdose:Mezavant is an aminosalicylate; signs of intoxication of salicylates include tinnitus, vertigo, headache, confusion, drowsiness, pulmonary edema, dehydration amid sweating, diarrhea and vomiting, hypoglycemia, hyperventilation, electrolyte imbalance and blood pH, hyperthermia.
In acute overdose, it is necessary to use standard methods of treatment of acute intoxication of salicylates. Hypoglycemia and disturbance of the water-electrolyte balance should be adjusted by appropriate therapy. Adequate renal function should be maintained.

Interaction:Clinical studies in adult healthy volunteers did not reveal clinically significant interactions of Mezavant with the 4 most commonly used antimicrobials (amoxicillin, ciprofloxacin, metronidazole and sulfamethoxazole).
Nevertheless, there are data on the interaction of other mesalazine-containing drugs with drugs:
- It is recommended to use caution mesalazine simultaneously with drugs that have a nephrotoxic effect, including non-steroidal anti-inflammatory drugs (NSAIDs) and azathioprine, since this may increase the risk of adverse events from the kidneys.
- Mesalazine inhibits the activity of thiopurin methyltransferase. It is recommended that you take it with care mesalazine concomitantly with azathioprine or mercaptopurine, as this may increase the risk of disrupting the cellular composition of the blood.
- The use of mesalazine together with anticoagulants of the coumarin group, for example, warfarin, may be accompanied by a decrease in activity of the latter. If this combination is necessary, prothrombin time should be carefully monitored.

Special instructions:When using drugs containing mesalazine or its precursors, cases of renal dysfunction are described, including minimal nephropathy and acute / chronic interstitial nephritis.Mezavant should be used with caution in patients with confirmed mild or moderate renal impairment. All patients are recommended to undergo a study of kidney function before treatment and at least 2 times a year during treatment.
Patients with chronic pulmonary dysfunction (asthma) have an increased risk of developing hypersensitivity reactions, and should be under constant supervision of medical personnel.
After receiving mesalazine in rare cases, a serious disruption of the cellular composition of the blood developed. When a patient has unexplained bleeding, bruising, purpura, anemia, fever, or sore throat, a blood test should be performed. If there is a suspicion of a disorder in the cellular composition of the blood, treatment should be discontinued. When using Mezavant or other preparations containing mesalazine, rare cases of reactions of hypersensitivity from the heart (myo- and pericarditis) are described. It should be cautious to prescribe this drug to patients with diseases predisposing to the development of myo- or pericarditis.If suspected of a hypersensitivity reaction, re-use of drugs containing mesalazine, is unacceptable.
The use of mesalazine is associated with the development of an acute intolerance syndrome, which in some cases is difficult to distinguish from an exacerbation of inflammatory bowel disease. Although the frequency of this phenomenon is not accurately established, it was 3% in controlled clinical trials of mesalazine or sulfasalazine. Symptoms include intestinal cramps, acute pain in the abdomen, diarrhea with an admixture of blood, sometimes a fever, a headache and a rash. If suspected of developing an acute intolerance syndrome, drugs containing mesalazine, and their repeated use is unacceptable.
There have been reports of an increase in the activity of "liver" transaminases in patients taking drugs containing mesalazine. It is recommended to be cautious when administering Mezavant to patients with impaired liver function.
Care should be taken when treating patients who are allergic to sulfasalazine, because of possible cross-sensitivity to mesalazine.
Organic or functional obstruction of the upper gastrointestinal tract can slow the development of the drug effect.
If renal dysfunction during the treatment of patients with the drug Mesavant should take into account mesalazine-induced nephrotoxicity.
The use of mesalazine can lead to falsely elevated test results in the measurement of normometine in urine using liquid chromatography with electrochemical detection due to the similarity of the chromatograms of normetanephrine and the main metabolite of mesalazine-N-Acetylaminosalicylic acid (N-Ac-5-ACA). Therefore, to determine the content of normetanephrine in urine, an alternative selective method should be used.

Effect on the ability to drive transp. cf. and fur:Studies of the effect of Mezavant on the ability to drive and move vehicles have not been carried out. It is believed that the drug Mezavant does not affect this ability.

Form release / dosage:Tablets of prolonged action, covered with an enteric coating of 1.2 g.

Packaging:For 12 tablets in a blister of polyamide / aluminum / PVC, covered with aluminum foil.For 5 blisters together with instructions for use in a pack of cardboard.

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

Shelf life:2 years.
Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-001297

Date of registration:28.11.2011 / 22.06.2016

Expiration Date:28.11.2016

The owner of the registration certificate:Shayer Pharmaceuticals Ayerland Co., Ltd.Shayer Pharmaceuticals Ayerland Co., Ltd. Ireland

Manufacturer: & nbsp

COSMO, S.p.A. Italy

Representation: & nbspJohnson & Johnson LLC Johnson & Johnson LLC Russia

Information update date: & nbsp2016-09-21

Illustrated instructions

Instructions

Mezavant® (Mezavant®)