Mezavant

General characteristics. Structure:

Active component: месалазин 1200 mg.

Excipients: Tablet kernel: sodium of a karmelloz (7MF) – 11,3 mg, sodium of a karmelloz (7HXF) – 38,7 mg, wax of karnaubskiya – 5,0 mg, stearic acid – 10,0 mg, silicon dioxide colloid – 2,0 mg, sodium carboxymethylstarch (type A) – 30,0 mg, talc – 11,0 mg, magnesium stearate – 14,0 mg. Tablet cover: talc – 17,8 mg, methacrylic acid and methylmethacrylate copolymer [1:1] – 16,0 mg, methacrylic acid and methylmethacrylate copolymer [1:2] – 16,0 mg, triethyl citrate – 3,2 mg, titanium dioxide – 6,0 mg, dye ferrous oxide red – 3,0 mg, a macrogoal of 6000 - 1,0 mg.

Description: Oblong biconvex tablets, coated red-brown color. On one party – an engraving of "S476". On cross section a tablet kernel from white till almost white color.

Pharmacological properties:

Action mechanism. Mesalazin is derivative 5-aminosalicylic acid. The mechanism of action of a mesalazin is up to the end not studied, but was established that drug has local antiinflammatory effect on an intestines epithelium. At patients with a chronic inflammatory disease of intestines in a mucous membrane synthesis of metabolites of arachidonic acid on cyclooxygenase and lipoksigenazny ways amplifies. Perhaps, месалазин weakens an inflammation by inhibition of cyclooxygenase and oppression of synthesis of prostaglandins in a large intestine. Mesalazin has ability to oppress activation of a nuclear factor kappa-V – NFKB and, therefore, products of key pro-inflammatory cytokines. Recently the assumption that insufficiency of nuclear receptors of PPAR-γ (a γ-shape of the receptors activated by a proliferator of peroxisomas) can be connected with development of ulcer colitis was made. Efficiency of agonists of receptors of PPAR-γ at ulcer colitis was shown. The accumulated data indicate that the effect of a mesalazin can be implemented by impact on PPAR-γ receptors.

Pharmacokinetics. The tablet of drug of Mezavant has the kernel containing месалазин (5-aminosalicylic acid, 5-ACK) in a multicomponent matrix. The kernel is surrounded with a cover from copolymers of methacrylic acid of types A and B; the cover is developed so that allocation of a mesalazin began only at achievement рН higher than 7.

The mechanism of action of a mesalazin is up to the end not studied, but it is considered that месалазин (5-ACK) has local effect therefore the clinical effect of drug does not correlate with pharmacokinetic characteristics of substance. The main way of removal of a mesalazin is metabolism to N-acetyl-5-aminosalicylic acid which pharmacological is inactive.

Absorption. Researches with carrying out gamma сцинтиграфии showed what after a single dose healthy volunteers of drug on an empty stomach in a dose of 1,2 g месалазин quickly and in not changed look passes through upper parts of digestive tract. At the same time traces of a 14C-mechenny mesalazin throughout a large intestine come to light that demonstrates receipt of a mesalazin in these departments of digestive tract. Full disintegration of a tablet of drug of Mezavant and release of a mesalazin it was observed approximately in 17,4 hours.

After a single dose of drug healthy volunteers in a dose of 2,4 g or 4,8 g within 14 days absorption of a mesalazin made 21 – 22% of the accepted dose.

After a single dose of drug on an empty stomach in a dose of 1,2 g, 2,4 g and 4,8 g concentration of a mesalazin in plasma was defined by healthy volunteers in 2 hours (median) after reception and reached the maximum value in 9 – 12 hours (median). Pharmacokinetic indicators showed wide variability. Level of system exposure of a mesalazin – AUC (the area under a curve "concentration – time") - at administration of drug in the range from 1,2 g to 4,8 g was proportional to the accepted dose. The maximum concentration (Cmax) of a mesalazin in plasma in the range of doses from 1,2 g to 2,4 g increased approximately in direct ratio whereas from 2,4 g increased to 4,8 g less, than in proportion to a dose.

When studying single and multiple dose of drug in a dose of 2,4 g and 4,8 g with usual food месалазин it was found in a blood plasma in 4 hours, reaching the maximum kotsentration in 8 hours after a single dose.

The single dose of drug of Mezavant in a dose of 4,8 g with greasy food was followed by delay of a phase of absorption. In these conditions месалазин it was found in a blood plasma approximately in 6 hours after reception. However the food rich with fats increased system exposure of a mesalazin (average Cmax value – for 91%, average AUC value – for 16%) in comparison with indicators on an empty stomach.

Distribution. It is considered that drug of Mezavant possesses a similar profile of distribution, as other mesalazin-containing drugs. Mesalazin has rather small volume of distribution, equal about 18 l that demonstrates the minimum system distribution. At concentration of a mesalazin in a blood plasma to 2,5 mkg/ml and concentration of N-acetyl-5-aminosalicylate to 10 mkg/ml of substance contacted proteins of a blood plasma for 43% and 78-83% respectively.

Metabolism. The only important metabolite of a mesalazin is pharmacological inactive N-acetyl-5-aminosalicylic acid. It is formed under the influence of N-acetyltransferase-1 in cells of a liver and cytosol of cells of a mucous membrane of intestines.

Removal: Soaked up месалазин it is removed generally by kidneys after acetylation to N-acetyl-5-aminosalicylic acid. Nevertheless, drug in a small amount is removed by kidneys and in not changed look. Less than 8% of a mesalazin are brought out of 21 – 22% of the soaked-up drug dose in not changed view with urine within 24 hours. About 13% are removed within 4 hours in the form of N-acetyl-5-aminosalicylic acid. The visible elimination half-life of a mesalazin and its main metabolite after administration of drug in a dose of 2,4 and 4,8 g were on average 7-9 and 8-13 hours respectively.

Special categories of patients. There are no data on use of drug of Mezavant for patients with an abnormal liver function. After a single dose of drug of Mezavant in a dose of 4,8 g system exposure of a mesalazin at elderly patients (65 years, average clearance of creatinine of 68-76 ml/min. are more senior) surpassed that at younger patients (18 – 35 years, average clearance of creatinine of 124 ml/min.) to 2 times. Level of system exposure is inversely proportional the function of kidneys estimated on clearance of creatinine. It should be considered at treatment of elderly patients drug of Mezavant.

At patients with a renal failure reduction in the rate of removal and increase in concentration of a mesalazin in a blood plasma can be observed that can be followed by increase in risk of undesirable side reactions from an urinary system.

At women the area under curve AUC ("concentration – time") the mesalazin was twice more, than at men.

Proceeding from the limited number of pharmacokinetic data, the pharmacokinetics 5-ACK and N-atsetil-5-ASK at faces of the South European and Spanish-speaking group is considered identical.

Indications to use:

Induction of remission on clinical and endoscopic indicators at patients with the weak or moderately expressed ulcer colitis. Maintenance of remission at patients with ulcer colitis. 

Route of administration and doses:

Drug of Mezavant is intended for oral administration during food once a day. Tablets cannot be crushed or chewed and it is necessary to swallow of them entirely.

Adults, including elderly (65 years are more senior). Remission induction: 2,4 – 4,8 g (2 – 4 tablets) once a day. For the patients not sensitive to the minimum dose, the recommended maximum daily dose makes 4,8 g. At reception of the maximum dose (4,8 g/days) the effect of treatment should be estimated in 8 weeks. Remission maintenance: 2,4 g (2 tablets) once a day.

Children and teenagers up to 18 years. Due to the lack of data on safety and efficiency drug of Mezavant is not recommended to be used at children 18 years are younger.

Special drug use studies of Mezavant at patients with disturbance of functions of a liver or kidneys it was not carried out. 

Features of use:

At use of the drugs containing месалазин or his predecessors, are described cases of a renal failure, including the minimum nephropathy and acute/chronic intersticial nephrite. Drug of Mezavant should be used with care at patients with the renal failure confirmed weak or moderately expressed. All patients are recommended to pass a research of function of kidneys before an initiation of treatment and, at least, 2 times a year during treatment.

Patients with chronic dysfunction of lungs (asthma), have the increased risk of development of reactions of hypersensitivity, and have to be under constant observation of medical personnel.

After reception of a mesalazin heavy disturbance of cellular composition of blood in rare instances developed. At emergence in sick inexplicable bleeding, bruises, a purpura, anemia, fervescence or pharyngalgia it is necessary to carry out blood test. At suspicion on disturbance of cellular composition of blood treatment should be stopped.

At use of drug of Mezavant or other drugs containing месалазин exceptional cases of reactions of hypersensitivity from heart are described (mio-and a pericardis). It is necessary to appoint with care this drug the patient with the diseases contributing to development mio-or a pericardis. At suspicion on hypersensitivity reaction, repeated use of the drugs containing месалазин, inadmissibly.

Use of a mesalazin is connected with development of an acute syndrome of intolerance which is in certain cases difficult for distinguishing from an exacerbation of an inflammatory disease of intestines. Though the frequency of this phenomenon is definitely not established, in controlled clinical trials of a mesalazin or Sulfasalazinum it made 3%. Symptoms include enterospasms, an acute pain in a stomach, diarrhea with blood impurity, sometimes temperature increase, a headache and rash. At suspicion on development of an acute syndrome of intolerance it is necessary to cancel immediately the drugs containing месалазин, and their repeated use is inadmissible.

The patients accepting the drugs containing месалазин have messages on increase in activity of "hepatic" transaminases. It is recommended to show care at purpose of drug of Mezavant the patient with an abnormal liver function.

It is necessary to show care at treatment of the patients having an allergy to Sulfasalazinum because of possible cross hypersensitivity to a mesalazin.

Organic or functional impassability of upper parts of a gastro intestinal path can slow down development of effect of drug.

At a renal failure during treatment of patients with drug of Mezavant it is necessary to consider the nephrotoxicity caused mesalaziny.

Use of a mesalazin can bring to in a false manner to the increased results of testing at measurement of maintenance of a normetanefrin in urine by means of liquid chromatography with electrochemical detection because of similarity хроматограмм a normetanefrin and the main metabolite of a mesalazin – N-atsetilaminosalitsilovoy of acid (N-Ac-5-ACA). Therefore for determination of content of a normetanefrin in urine the alternative selection method has to be used.

Influence on ability to drive the car and other mechanical means. Researches of influence of drug of Mezavant on ability to drive the car and moving mechanisms were not conducted. It is considered that drug of Mezavant does not exert impact on this ability. 

 

Side effects:

The headache, pain in a stomach and nausea were the most often arising by-effects during clinical trials. For one undesirable side reaction frequency did not exceed 10%. At use of drug of Mezavant other side reactions were observed less often.

Undesirable reactions of drug of Mezavant, and also the undesirable reactions which arose at reception of other mesalazin-containing drugs are systematized concerning each of systems of bodies with use of the following classification of frequency of occurrence:

Very often (≥1/10)

Often (≥1/100, <1/10)

Infrequently (≥1/1000, <1/100)

Seldom (≥1/10000, <1/1000)

Very seldom (<1/10000), including isolated cases

From blood and lymphatic system:

- infrequently: thrombocytopenia;

- seldom: agranulocytosis;

- frequency is unknown: aplastic anemia, leukopenia, neutropenia, pancytopenia.

From the central nervous system:

- often: headache;

- infrequently: dizziness, drowsiness, tremor;

- frequency is unknown: neuropathy.

From cardiovascular system:

- often: increase in arterial pressure;

- infrequently: tachycardia, hypotonia;

- frequency is unknown: myocarditis, pericardis.

From respiratory system:

- infrequently: drink/throat pain;

- frequency is unknown: bronchospasm.

From digestive tract:

- often: abdominal distention, abdominal pain, diarrhea, dyspepsia, vomiting, meteorism, nausea, deviation of indicators of functional hepatic trials (aspartate aminotransferase, alaninaminotranspherase, bilirubin);

- infrequently: colitis, pancreatitis, rectum polyp;

- frequency is unknown: hepatitis, cholelithiasis.

From skin and hypodermic fabrics:

- often: itch, rash;

- infrequently: acne rashes, alopecia.

From immune system:

- infrequently: small tortoiseshell;

- frequency is unknown: a pneumonitis as hypersensitivity manifestation (including an intersticial pneumonitis, an allergic alveolitis, an eosinophilic pneumonitis), the Quincke's disease, a syndrome similar to a system lupus erythematosus, anaphylactic reaction, Stephens-Johnson's syndrome, the medicinal skin reaction which is followed by an eosinophilia and system manifestations (DRESS).

From a musculoskeletal system, connecting and bone tissue:

- often: the arthralgia accompanying muscle pain, a dorsodynia;

- infrequently: mialgiya.

From urinogenital system:

- seldom: renal failure;

- frequency is unknown: intersticial nephrite.

General state:

- often: adynamy, fervescence;

- infrequently: face edema, weakness. 

Interaction with other medicines:

Clinical trials on adult healthy patients did not reveal clinically significant interactions of drug of Mezavant with 4 the most often used antibiotics (amoxicillin, ciprofloxacin, metronidazole and sulfamethoxazole).

Nevertheless there are data on interaction of other mesalazin-containing drugs with medicines: 

- It is recommended to apply with care месалазин along with the drugs having nephrotoxic effect including with non-steroidal anti-inflammatory drugs (NPVP) and Azathioprinum as at the same time the risk of development of the adverse phenomena from kidneys can increase. 

- Mesalazin inhibits activity of thiopurinemethyltransferase. It is recommended to take with caution месалазин along with Azathioprinum or Mercaptopurinum as it can increase risk of disturbance of cellular composition of blood.

Use of a mesalazin together with anticoagulants of group of coumarin, for example, warfarin, can be followed by decrease of the activity of the last. In need of use of such combination it is necessary to control a prothrombin time carefully. 

Contraindications:

- Hypersensitivity to salicylates (including месалазин) or to any auxiliary component of drug.

- Heavy disturbance of functions of kidneys (SKF <30 ml/min. / 1,73 sq.m). 

- Heavy disturbance of functions of a liver. 

- Children's age up to 18 years (due to the lack of data on safety and efficiency of drug at this category of patients).

With care:

- the easy or moderately expressed renal failure; 

- chronic dysfunction of lungs (bronchial asthma);

- the diseases contributing to development mio-or a pericardis;

- drug with care is appointed the patient having an allergy to Sulfasalazinum because of possible cross hypersensitivity to a mesalazin.

Overdose:

Drug of Mezavant is an aminosalicylate; symptoms of intoxication of salicylates include a sonitus, вертиго, a headache, confusion of consciousness, drowsiness, a fluid lungs, dehydration against the background of the increased sweating, diarrheas and vomitings, a hypoglycemia, a hyperventilation, disturbance of electrolytic balance and рН blood, a hyperthermia.

At acute overdose it is necessary to apply standard methods of treatment of acute intoxication of salicylates. The hypoglycemia and disturbance of water and electrolytic balance should be adjusted by the corresponding therapy. It is necessary to support adequate function of kidneys. 

Storage conditions:

To store in original packaging at a temperature not above 25 °C. To store in the place, unavailable to children. To store in original packaging for protection against moisture. 

Issue conditions:

According to the recipe

Packaging:

The tablets of the prolonged action covered with a kishechnorastvorimy cover of 1,2 g. On 12 tablets in the blister from polyamide/aluminium/PVC covered with aluminum foil. On 5 blisters together with the application instruction in a pack cardboard.