Neksium

General characteristics. Structure:

Active agents: 22,3 mg or 44,5 mg of esomeprazole of magnesium of trihydrate that there correspond 20 mg and 40 mg of esomeprazole.
excipients: glyceryl monostearate 40-55, a hypro rod, a gipromelloza, ferrous oxide red, ferrous oxide yellow (for a dosage of 20 mg), magnesium stearate, methacrylic and etakrilovy acids copolymer (1:1), cellulose microcrystallic, paraffin synthetic, a macrogoal, polysorbate 80, кросповидон, the sodium stearylfumarating sucrose spherical granules, titanium dioxide, talc, triethyl citrate.

Description:

Tablets of 20 mg: An oblong biconvex tablet of light pink color in a cover, on the one hand an engraving of 20 mG, on the other hand –
Tablets of 40 mg: an oblong double and convex tablet of pink color in a cover, on the one hand an engraving of 40 mG, on the other hand -
Color on a break white with yellow impregnations (like a croup).

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 once 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).
At patients with the gastroesophageal reflux disease (GRD) and existence of clinical symptoms in 5 days of daily oral administration of esomeprazole in a dose of 20 mg or 40 mg 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 Neksium's reception 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 Neksium in a dose of 20 mg 2 times a day in a combination with the corresponding antibiotics within one 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 an acid secretion inhibition vyrazhenna. Cysts high-quality also have reversible character.
During two conducted comparative researches with ranitidine Neksium showed the best efficiency concerning healing of stomach ulcers at the patients receiving non-steroidal anti-inflammatory drugs (NPVP) including the selection inhibitors of cyclooxygenase-2 (TsOG-2).
During two researches Neksium showed high performance 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 once 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. Ezomsprazol 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, generally 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 once 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 once 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). Such patients have an esomeprazole metabolism, 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 once a day distinctions in pharmacokinetics at men and women are 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 a renal failure was not 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 was similar to AUC and tmax values at adults.

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
As a part 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 or other states which are characterized by pathological hypersecretion including, and idiopathic hypersecretion.

Route of administration and doses:

Inside. It is necessary to swallow of a tablet entirely, washing down with liquid. Tablets cannot be chewed or split up.
For patients with difficulty of swallowing it is possible to dissolve tablets in half of glass of still water (it is not necessary to use other liquids as the protective cover of microgranules can be dissolved), stirring to a tablet raspadeniye then the suspension of microgranules should be drunk at once or within 30 minutes then again to fill a glass with water half, to stir the remains and to drink. It is not necessary to chew or split up microgranules. For patients who cannot swallow tablets should be dissolved in still water and to enter via the nazogastralny probe. It is important that the chosen syringe and the probe were carefully tested. Instructions on preparation and administration of drug via the nazogastralny probe are provided in the section "Administration of Drug via the Nazogastralny Probe".
 
Adults and children since 12 years
 
Gastroesophageal reflux disease
Treatment erosive reflux esophagitis: on 40 mg once 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 once a day.
Symptomatic treatment of a gastroesophageal reflux disease: 20 mg once in days - 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 Neksium 20 mg once 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: Neksium of 20 mg, amoxicillin of 1 g and кларитромицин 500 mg. All drugs are accepted two times a day within 1 week.
• prevention of a recurrence of the round ulcers associated with Helicobacter pylori: Neksium of 20 mg, amoxicillin I of and кларитромицин 500 mg. All drugs are accepted two times a day within 1 week.
Patients, it is long the accepting NPVP:
• healing of the stomach ulcer connected with reception of NPVP: Neksium of 20 mg or 40 mg once a day. Duration treatment makes 4-8 weeks.
• Prevention of the stomach ulcer and a duodenum tied with reception of NPVP: Neksium of 20 mg or 40 mg once a day.
 The states connected with pathological hypersecretion, including, Zollingera-Ellison's syndrome and idiopathic hypersecretion
The recommended initial dose - Neksium of 40 mg two 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 120 mg 2 times a day.
 
Renal failure: dose adjustment of drug is not required. However, experience of use of Neksium 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").
Liver failure: 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.
 
Administration of drug via the nazogastralny probe
 
At purpose of drug via the nazogastralny probe
1. Place a tablet in the syringe and fill the syringe of 25 ml of water and about 5 ml of air. For some probes cultivation of drug in 50 ml of drinking water can be required to prevent a probe contamination tablet granules.
2. Immediately shake up the syringe within about two minutes for dissolution of a tablet.
3. You hold the syringe a tip up and be convinced that the tip did not get littered.
4. Enter a tip of the syringe and the probe, continuing to hold it directed up.
5. Stir up the syringe and turn it a tip down. Immediately enter 5-10 ml of the dissolved drug into the probe. After introduction return the syringe to former situation and shake up (the syringe has to be kept by a tip for avoidance of a contamination of a tip up).
6. Turn the syringe a tip down and enter 5-10 more ml of drug into the probe. Repeat this operation until the syringe is empty.
7. In case of the rest of a part of drug in the form of a deposit in width fill the syringe of 25 ml of water and 5 ml of air and repeat the operations described in point 5. 50 ml of drinking water can be necessary for some probes for this purpose.

Features of use:

In the presence of any alarming symptoms (for example, such as considerable spontaneous loss of body weight, repeated vomiting, a dysphagy, vomiting with impurity a sketch map 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 Neksium can lead to smoothing of symptomatology and delay 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 Neksium "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 Interaction"). At appointment Neksiuma for an eradikation of Helicobacter pylori has to be considered 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. Neksium's tablets contain sucrose therefore they are contraindicated to patients with hereditary intolerance of fructose, glyukozo-galaktozny malabsorption or sakharazo-izomaltazny insufficiency.
 
Influence on ability to drive the car and other mechanisms. Drug does not influence ability to drive the car and to manage mechanisms.
 
With care - a heavy renal failure (experience of use is limited).
 
Use during pregnancy and chest feeding. There is no enough data on Neksium's use during pregnancy now. Results of epidemiological researches of the omeprazol representing racemic mix showed lack of fetotoksichesky action or disturbance of fetation. At administration of esomeprazole the animal did not reveal any direct or indirect negative impact on development of an embryo or a fruit. Administration of racemic mix of drug also did not make any negative impact on animals during pregnancy, childbirth, and also during post-natal development.
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 it is allocated ззомепразол with breast milk therefore it is not necessary to appoint Neksium during feeding a breast.

Side effects:

The side effects which are not depending on a drug dose are included below.

 

Frequent (> 1/100, <1/10)	Headache, abdominal pain, diarrhea, meteorism, nausea/vomiting, lock
Less frequent (> 1/1000, <1/100)	Dermatitis, itch, urticaria, rash, dizziness, dryness in a mouth, sleeplessness, paresthesia, drowsiness, increase in activity of "hepatic" enzymes, peripheral hypostases
Rare (> 1/10000, <1/1000)	Leukopenia, thrombocytopenia, allergic reactions: fever, a Quincke's disease, anaphylactoid reaction, excitement, a depression, confusion, changes of taste and a hyponatremia, a sight illegibility, a bronchospasm, stomatitis and gastrointestinal candidiasis, hepatitis with (or without) jaundice, a photosensitization, an alopecia, an arthralgia, a mialgiya, an indisposition.
Very rare (<1/10000)	Agranulocytosis, pancytopenia, hallucinations (it is preferential at the weakened patients), agressive behavior, liver failure, hepatic encephalopathy, multiformny exudative erythema, Stephens-Johnson's syndrome. Toxic epidermal necrolysis, muscular weakness, intersticial nephrite, gynecomastia.

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 once days and an atazanavir of 300 mg / ритонавира led 100 mg to essential decrease in AUC values, and also 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 takes part. such as diazepam, to tsitalopra, Imipraminum, кломипрамин, Phenytoinum, etc., 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 Neksium's appointment 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 Neksium's addition did not increase (see the section "Special Instructions").
Neksium 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, the vorikonazola, can lead to more than 2-fold increase in AUC value for esomeprazole. In such cases esomeprazole dose adjustment is not required.

Contraindications:

Hypersensitivity to esomeprazole, the replaced benzimidazoles go to other ingredients which are a part of drug.
Hereditary intolerance of fructose, glyukozo-galaktozny malabsorption or sakharazo-izomaltazny insufficiency.
The children's age up to 12 years (due to the lack of data on efficiency and safety of use of drug for this troupe of patients) and children's age is more senior than 12 years on others indications except a gastroesophageal reflux disease.
Esomeprazole, as well as other inhibitors of a proton pomp, should not be accepted together with atazanaviry.

Overdose:

Extremely exceptional cases of intentional overdose are currently described. Oral administration of esomeprazole in a dose of 280 mg was followed by the general weakness and symptoms from digestive tract. One-time reception of 80 mg of Neksium did not cause any negative effects. Specific antidotes are unknown. Esomeprazole contacts proteins of plasma therefore dialysis is ineffective. In case of overdose it is necessary to carry out the symptomatic and general supporting treatment.

Storage conditions:

At a temperature not above 30 °C, in original packaging, in places unavailable to children. A period of validity - 3 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets, coated on 20 mg and 40 mg. On 7 tablets in the blister from PVC Is scarlet/. In a cardboard pack one, two or four blisters with the application instruction.