Эзокс

General characteristics. Structure:

Active ingredient: esomeprazole;

1 tablet contains trihydrate magnesium esomeprazole in terms of esomeprazole 20 mg or   40 mg;

excipients: cellulose microcrystallic, a mannitol (Е 421), sodium stearate, a gidroksipropilmetiltsellyuloza, talc, methacrylate copolymer (type C), polysorbate 80, polyethyleneglycol 6000, sodium hydroxide, опадрай II 33G53388 orange (a gipromelloza, lactoses monohydrate, titanium dioxide (Е 171), polyethyleneglycol, FCF "yellow decline" dye (Е 110), triacetin, ferrous oxide red krakhmalglikolit (type A), magnesium (Е 172).

Pharmacological properties:

Pharmacodynamics. Esomeprazole is S-isomer of an omeprazol; reduces secretion of acid in a stomach by specific inhibition of the proton pump in covering cells. S-and R-isomers of an omeprazol have similar pharmakodinamichesky activity.

Action mechanism. Esomeprazole is the weak basis, collects in secretory tubules of covering cells in acid medium where it is activated and inhibits the proton pump – H+, K enzyme +-Atfazu. Esomeprazole inhibits both basal, and stimulated secretion of acid.

Influence on secretion of acid in a stomach. Effect of esomeprazole develops within 1 hour after oral administration of 20 mg or 40 mg. At daily administration of drug within      5 days in a dose of 20 mg of 1 times a day average maximum concentration of acid after stimulation by Pentagastrinum decreases by 90% (at measurement of concentration of acid in 6-7 hours after administration of drug for the 5th day of therapy).

Patients with a gastroesophageal reflux disease have (GERB) and existence of clinical symptoms in 5 days of daily oral administration of esomeprazole in a dose of 20 mg or    40 mg a value intragastric рН higher than 4 was maintained within, on average, 13 and    17 hours from 24 hours. Against the background of reception of esomeprazole in a dose of 20 mg a day value intragastric рН higher than 4 was maintained not less than 8, 12 and 16 hours at 76%, 54% and 24% of patients, respectively. For 40 mg of esomeprazole this ratio makes 97%, 92% and 56% respectively.

Correlation between concentration of drug in plasma and acid secretion inhibition (for assessment of concentration used the AUC parameter is revealed (the area under a curve concentration time).

The therapeutic effect reached as a result of acid secretion inhibition. At reception of esomeprazole in a dose of 40 mg healing the reflux esophagitis comes approximately at 78% of patients in 4 weeks of therapy and at 93% – in 8 weeks of therapy.

Treatment by esomeprazole in a dose of 20 mg 2 times a day in a combination with the corresponding antibiotics within 1 week leads to a successful eradikation of Helicobacter pylori approximately at 90% of patients.

Patients with an uncomplicated peptic ulcer after a week eradikatsionny course do not need the subsequent monotherapy by anti-secretory drugs for healing of an ulcer and elimination of symptoms.

Other effects connected with acid secretion inhibition. During treatment by anti-secretory drugs gastrin level in plasma increases as a result of decrease in secretion of acid.

At patients, the long time receiving esomeprazole, is noted increase in quantity of enterokhromaffinopodobny (ECL) cells probably connected with increase in level of gastrin in plasma.

At the patients accepting anti-secretory drugs during a long period formation of ferruterous cysts in a stomach is more often noted. These phenomena are caused by physiological changes in result of the expressed acid secretion inhibition. Cysts high-quality also have reversible character.

Esomeprazole is effective concerning healing of stomach ulcers at the patients receiving non-steroidal anti-inflammatory drugs (NPVP) including the selection inhibitors of cyclooxygenase-2 (TsOG-2). Esomeprazole is also effective concerning prevention of stomach ulcers and a duodenum at the patients receiving NPVP (the age group is more senior than 60 years and/or with a round ulcer in the anamnesis), including the selection   TsOG-2 inhibitors.

Pharmacokinetics. Absorption and distribution. Esomeprazole is unstable in acid medium therefore for oral administration use the tablets containing drug granules which cover is steady against action of a gastric juice. In the conditions of in vivo only an insignificant part of esomeprazole turns into R-isomer. Drug is quickly absorbed: the maximum concentration in plasma is reached in 1-2 hours after reception. Absolute bioavailability of esomeprazole after a single dose of a dose of 40 mg makes 64% and increases up to 89% against the background of daily reception of 1 times a day. For a dose of 20 mg of esomeprazole these indicators make 50% and 68%, respectively. Distribution volume at equilibrium concentration at healthy people makes about 0,22 l/kg of body weight. Esomeprazole contacts proteins of plasma for 97%. Meal slows down and reduces absorption of esomeprazole in a stomach, however it has no significant effect on efficiency of inhibition of secretion of hydrochloric acid.

Metabolism and excretion. Esomeprazole is exposed to metabolism with participation of system of P450 (CYP) cytochrome. The main part is metabolized with the participation of the specific polymorphic CYP2C19 isoform, at the same time hydroxies - and demetilirovanny metabolites of esomeprazole are formed. Metabolism of the rest is carried out by other specific CYP3A4 isoform; at the same time it is formed sulfoderivative esomeprazole, being the main metabolite defined in plasma.

The parameters specified below reflect in the basic character of pharmacokinetics at patients with active CYP2C19 enzyme (patients with active metabolism).
The general clearance makes about 17 l/h after a single dose of drug and 9 l/h – after multiple dose. The elimination half-life makes 1,3 hours at systematic reception of 1 times a day. The area under a curve concentration time (AUC) increases at repeated reception of esomeprazole. Dozozavisimy increase in AUC at repeated reception of esomeprazole has nonlinear character that is a consequence of decrease in metabolism at the first passing through a liver, and also decrease in system clearance probably of the CYP2C19 enzyme caused by inhibition esomeprazole and/or its sulfocontaining metabolite. At daily reception of 1 times a day esomeprazole is completely removed from a blood plasma in a break between receptions and does not kumulirut.

The main metabolites of esomeprazole do not influence secretion of gastric acid. At oral administration to 80% of a dose it is removed in the form of metabolites with urine, other quantity is removed with excrements. In urine less than 1% of not changed esomeprazole are found.
Features of pharmacokinetics in some groups of patients. Approximately at 1-2% of the population CYP2C19 enzyme малоактивен (patients with inactive metabolism). At such patients metabolism of esomeprazole is generally carried out as a result of action of CYP3A4. At systematic reception of 40 mg of esomeprazole once in days average AUC value for 100% exceeds value of this parameter at patients with active CYP2C19 enzyme (patients with bystry metabolism). Average values of the maximum concentration in plasma at patients with slow metabolism are increased approximately for 60%. The specified features do not influence a dosage and a route of administration of esomeprazole.

At patients of advanced age (71-80 years) metabolism of esomeprazole does not undergo considerable changes.

After a single dose of 40 mg of esomeprazole average AUC value at women for 30% exceeds that at men. At daily administration of drug of 1 times in days of distinctions in pharmacokinetics at men and women it is not noted. The specified features do not influence a pas a dosage and a route of administration of esomeprazole.

At patients with a slight and moderate liver failure metabolism of esomeprazole can be broken. At patients with a heavy liver failure the speed of metabolism is reduced that leads to increase in AUC value for esomeprazole twice.

Studying of pharmacokinetics at patients with the renal nedostatochnostyena was carried out. As through kidneys removal not esomeprazole, and its metabolites is carried out, it is possible to believe that metabolism of esomeprazole at patients with a renal failure does not change.

Children at the age of 12-18 years after repeated reception have 20 mg and 40 mg of esomeprazole AUC value and time of achievement of the maximum concentration (tmax) in a blood plasma is similar to AUC and tmax values at adults.

Pharmaceutical characteristics.

Main physical and chemical properties: tablets of light brown color, oblong shape, biconvex, coated, kishechnorastvorimy.

Indications to use:

Gastroesophageal reflux disease:

· treatment erosive reflux esophagitis;

· the prolonged supporting treatment after healing erosive a reflux esophagitis for prevention of a recurrence;

· symptomatic treatment of a gastroesophageal reflux disease.

Peptic ulcer of a stomach and duodenum (vsostava of a combination therapy):

· treatment of an ulcer of the duodenum associated with Helicobacter pylori;

· prevention of a recurrence of the round ulcer associated with Helicobacter pylori.
Patients, it is long the accepting NPVP:

· healing of the stomach ulcer connected with reception of NPVP;

· prevention of the stomach ulcer and a duodenum tied with reception of NPVP at the patients belonging to risk group.

Zollingera-Ellison's syndrome.

Route of administration and doses:

Drug is appointed in inside. Tablets should be washed down with enough liquid. Tablets should not be chewed.

Adults and children since 12 years.

Gastroesophageal reflux disease.

Treatment erosive reflux esophagitis: on 40 mg of 1 times a day during 4 loops.
The additional 4-week course of treatment in cases when after the first course healing of an esophagitis does not occur is recommended or symptoms remain.

The prolonged supporting treatment after healing erosive a reflux esophagitis for prevention of a recurrence: on 20 mg of 1 times a day.

Symptomatic treatment of a gastroesophageal reflux disease: 20 mg of 1 times a day – to patients without esophagitis. If after 4 weeks of treatment symptoms do not disappear, it is necessary to conduct additional examination of the patient. After elimination of symptoms it is possible to switch over to the mode of administration of drug if necessary, i.e. to accept esomeprazole on 20 mg of 1 times a day when resuming symptoms. For the patients accepting NPVP and belonging to risk group of development of stomach ulcer or a duodenum treatment in the mode "in need of" is not recommended.

Adults.

Peptic ulcer of a stomach and duodenum.

As a part of a combination therapy for an eradikation with Helicobacter pylori:

· treatment of an ulcer of the duodenum associated with Helicobacter pylori: esomeprazole of 20 mg, amoxicillin of 1 g and кларитромицин 500 mg. To accept all drugs 2 times a day within 1 week.

· prevention of a recurrence of the round ulcers associated with Helicobacter pylori: esomeprazole of 20 mg, amoxicillin I of and кларитромицин 500 mg. To accept all drugs 2 times a day within 1 week.

Patients, it is long the accepting NPVP:

· healing of the stomach ulcer connected with reception of NPVP: Эзокс 20 mg or 40 mg of 1 times a day. Duration treatment makes 4-8 weeks.

· Prevention of the stomach ulcer and a duodenum tied with reception of NPVP: Эзокс 20 mg or 40 mg of 1 times a day.

Zollingera-Ellison's syndrome.

The recommended initial dose – Ezoks of 40 mg 2 times a day. Further the dose is selected individually, duration of treatment is defined by a clinical picture of a disease. There is an experience of use of drug and doses to 80 mg 2 times a day.

Disturbances of functions of kidneys. Dose adjustment of drug is not required. However experience of use of esomeprazole for patients with a heavy renal failure is limited; in this regard, at purpose of drug such patients should be careful (see the section Pharmacokinetics).

Disturbances of functions of a liver. At a slight and moderate liver failure dose adjustment of drug is not required. For patients with a heavy liver failure it is not necessary to exceed the maximum daily dose – 20 mg.

Patients of advanced age. Dose adjustment of drug is not required.

Features of use:

Use during pregnancy or feeding by a breast.

There is no enough data on use of esomeprazole during pregnancy now.

It is necessary to appoint drug pregnant only in that case when the expected advantage for mother exceeds possible risk for a fruit.

It is unknown whether gets ззомепразол into breast milk therefore it is not necessary to appoint Ezoks during feeding a breast.

Children.

Эзокс appoint to children 12 years only with a gastroesophageal reflux disease as are absent given concerning its use to children up to 12 years at other pathology are more senior.

In the presence of any alarming symptoms (for example, such as considerable spontaneous loss of body weight, repeated vomiting, a dysphagy, vomiting with impurity of blood or a melena), and also in the presence of stomach ulcer (or at suspicion of stomach ulcer) it is necessary to exclude existence of a malignant new growth as treatment by esomeprazole can lead to smoothing of symptomatology and delay establishment of the diagnosis.

The patients accepting drug during the long period (especially over a year) have to be under regular observation of the doctor.

The patients accepting Ezoks as necessary have to be instructed about need to contact the doctor at change of character of symptoms. In view of fluctuations of concentration of esomeprazole in plasma at purpose of therapy as necessary, it is necessary to consider interaction of drug with other medicines (see the section Interaction with other medicines and other types of interactions).

At Ezoks's appointment for an eradikation of Helicobacter pylori it is necessary to consider a possibility of medicinal interactions for all components of triple therapy. Klaritromitsin is powerful CYP3A4 inhibitor therefore at purpose of eradikatsionny therapy to the patients receiving other drugs which are metabolized with participation of CYP3A4 (for example, a tsisaprida), it is necessary to consider possible contraindications and interactions of a klaritromitsin with these medicines.

Ability to influence speed of response at control of motor transport or work with other mechanisms.

Due to the possible development of side reactions from the central nervous system of driving or work with other mechanisms is contraindicated.

Side effects:

The phenomena are undesirable were classified depending on emergence frequency: often (> 1/100, <1/10); infrequently (> 1/1000, <1/100); seldom (> 1/10 000, <1/1000) and it is very rare   (<1/10 000).

Disturbance of system of blood and lymph: seldom – a leukopenia, thrombocytopenia; very seldom – an agranulocytosis, a pancytopenia.

Disturbance of immune system: seldom – hypersensitivity reactions, such, as, fever, a Quincke's disease and an acute anaphylaxis. 

Metabolism disturbance: infrequently – peripheral hypostases; seldom – a hyponatremia.
Mental disorders: infrequently – sleeplessness; seldom – excitement, a depression, confusion of consciousness; very seldom – aggression, hallucinations.

Disturbances of a nervous system: often – a headache; infrequently – weakness, paresthesia, drowsiness, dizziness; seldom – taste disturbances.

Vision disorders: seldom – a sight illegibility.

Disturbances of respiratory system: seldom – a bronchospasm.

Disturbance of the alimentary system: often – an abdominal pain, locks, diarrhea, abdominal distention, nausea, vomiting; infrequently – dryness in a mouth; seldom – stomatitis, digestive tract candidiasis.

Disturbance of gepatobiliarny system: infrequently – increase in level of liver enzymes; seldom – hepatitis with (without) jaundice; very seldom – a liver failure, encephalopathy at patients with liver diseases.

Disturbance of skin and soft tissues: infrequently – dermatitis, an itch, rash; seldom – an alopecia, photosensitivity; very seldom – a multiformny erythema, Stephens-Johnson's syndrome, a toxic epidermal necrolysis.

Skeletal and muscular disturbances: seldom – an arthralgia, a mialgiya; very seldom – muscular weakness.
Narvsheniya from kidneys and an urinary system: very seldom – intersticial nephrite.

Narvsheniya reproductive system: very seldom – a gynecomastia.

General disturbances: seldom – weakness, sweating strengthening.

Interaction with other medicines:

Influence of esomeprazole on pharmacokinetics of other medicines.

Decrease in acidity of a gastric juice against the background of treatment by esomeprazole can lead to change of absorption of drugs which absorption depends on acidity of the environment. Esomeprazole as the antacids and other drugs reducing secretion of acid in a stomach can lead to decrease in absorption of a ketokonazol and itrakonazol.
Joint purpose of an omeprazol in a dose of 40 mg of 1 times a day and an atazanavir of 300 mg / ритонавира led 100 mg to essential decrease in AUC values, and also to the maximum and minimum concentration of an atazanavir at healthy volunteers. Increase in a dose of an atazanavir up to 400 mg did not compensate influence of an omeprazol on concentration of an atazanavir. Therefore it is not necessary to appoint esomeprazole together with atazanaviry.

Esomeprazole inhibits CYP2C19 – the main enzyme participating in his metabolism. Respectively, combined use of esomeprazole with other drugs in which metabolism CYP2C19, such as diazepam, to tsitalopra, Imipraminum, кломипрамин, Phenytoinum, etc. takes part can lead to increase in concentration of these drugs in plasma that, in turn, can demand decrease in a rod. It is especially important to remember this interaction at purpose of esomeprazole in the mode as necessary. At joint reception of 30 mg of esomeprazole and diazepam which is CYP2C19 cytochrome substrate, decrease in clearance of diazepam by 45% is noted.

Purpose of esomeprazole in a dose of 40 mg led to increase in residual concentration of Phenytoinum at patients with epilepsy for 13%. In this regard it is recommended to control concentration of Phenytoinum in plasma in an initiation of treatment esomeprazole and at its cancellation.

Joint reception of warfarin from 40 mg of esomeprazole does not lead to change of time of coagulation at patients, is long accepting warfarin. However it was reported about several cases of clinically significant increase in the MHO index (the international normalized relation) at combined use of warfarin and esomeprazole. It is recommended to control MHO at the beginning and upon termination of combined use of esomeprazole and warfarin or other derivatives of coumarin.

Joint reception of a tsizaprid from 40 mg of esomeprazole leads to increase in values of pharmacokinetic parameters of a tsizaprid at healthy volunteers: AUC – for 32% and an elimination half-life for 31%, however the maximum tsizaprida of concentration in plasma at the same time considerably does not change.

Insignificant lengthening of an interval of QT which was observed at monotherapy tsizapridy at addition of esomeprazole did not increase (see the section of Feature of use).

Esomeprazole does not cause clinically significant changes of pharmacokinetics of amoxicillin and quinidine.

Researches on assessment of short-term combined use of esomeprazole and Naproxenum or rofekoksib did not reveal clinically significant pharmacokinetic interaction.

Influence of medicines on esomeprazole pharmacokinetics.

CYP2CI9 and CYP3A4 take part in metabolism of esomeprazole.
Combined use of esomeprazole with klaritromitsiny (500 mg 2 times a day) which inhibits CYP3A4, leads to increase in AUC value of esomeprazole twice. Combined use of esomeprazole and the combined CYP3A4 and CYP2C19 inhibitor, for example, of a vorikonazol, can lead to more than double increase in AUC value for esomeprazole. In such cases esomeprazole dose adjustment is not required.

Contraindications:

Hypersensitivity to esomeprazole, to the replaced benzimetazolama or to other components of drug.

Esomeprazole, as well as other inhibitors of a proton pomp, it is impossible to apply together with atazanaviry.
The children's age up to 12 years (due to the lack of data on efficiency and safety of use of drug for this group of patients) and children's age is more senior than 12 years according to other indications, except a gastroesophageal reflux disease.

Overdose:

Extremely exceptional cases of intentional overdose are currently described. Symptoms: at oral administration of esomeprazole in a dose of 280 mg also symptoms from digestive tract are noted the general by weakness. One-time reception of esomeprazole in a dose of 80 mg does not cause serious negative consequences.

Treatment: if necessary carry out the symptomatic and general supporting treatment. The specific antidote is unknown. Dialysis is ineffective because esomeprazole contacts proteins of plasma.

Storage conditions:

Period of validity. 2 years from day of production of "in bulk". To store in the place, unavailable to children, in original packaging at a temperature not over 25 ºС.

Issue conditions:

According to the recipe

Packaging:

On 5 tablets in a blister strip packaging. On the 3rd blister strip packagings in a pack.