Esomeprazol-native - instructions for use, dose, side effects, contraindications

Esomeprazole is S-isomer of omeprazole and reduces the secretion of hydrochloric acid in the stomach by specifically inhibiting the proton pump in parietal cells of the stomach. S- and Romeprazole isomers have similar pharmacodynamic activity.

Mechanism of action

Esomeprazole is a weak base that transforms into an active form in a highly acidic environment of the secretory tubules of the parietal cells of the gastric mucosa and inhibits the proton pump, the enzyme H⁺/TO⁺-ATPase, thus inhibiting both basal and stimulated secretion of hydrochloric acid.

Effect on the secretion of hydrochloric acid in the stomach

After ingestion of esomeprazole at a dose of 20 mg or 40 mg for 5 days, patients with gastroesophageal reflux disease (GERD), with symptoms, showed a decrease in the secretion of hydrochloric acid in the stomach for most of the day. The effect was the same for intravenous administration and for oral administration.

The analysis of pharmacokinetic data revealed the relationship between inhibition of hydrochloric acid secretion and esomeprazole concentration in the blood plasma after oral administration (to estimate the concentration, the parameter AUC - area under the curve "concentration-time").

Against intravenous administration of esomeprazole at a dose of 80 mg for 30 minutes followed by a prolonged intravenous infusion of esomeprazole at a dose of 8 mg / h for 23.5 hours, the gastric pH was above 4 for an average of 21 hours and above 6 - within 11-13 hours.

The therapeutic effect achieved by inhibiting the secretion of hydrochloric acid

Erection of reflux esophagitis with oral administration of esomeprazole at a dose of 40 mg occurs in approximately 78% of patients after 4 weeks of therapy and in 93% of patients after 8 weeks of therapy.

The efficacy of esomeprazole in bleeding from peptic ulcers confirmed endoscopically is shown.

Other effects associated with inhibition of hydrochloric acid secretion

During treatment with drugs that reduce the secretion of the glands of the stomach, the concentration of gastrin in the blood plasma increases as a result of a decrease in the secretion of hydrochloric acid. Due to a decrease in the secretion of hydrochloric acid, the concentration of chromogranin A (CgA). Increase in concentration CgA can influence the results of examinations for the detection of neuroendocrine tumors.To prevent this effect, therapy with proton pump inhibitors should be stopped 5 to 14 days before the study concentration CgA. If during this time the concentration CgA did not return to the normal value, the study should be repeated.

In children and adult patients who took esomeprazole inside for a long period of time, there was an increase in the number of enterochromaffin-like cells, which is probably due to an increase in the concentration of gastrin in the blood plasma. Clinical significance of this phenomenon is not.

In patients who took orally for a long time, drugs that reduce the secretion of the glands of the stomach, the formation of glandular cysts in the stomach was more often noted. These phenomena are caused by physiological changes due to inhibition of hydrochloric acid secretion. Cysts are benign and undergo reverse development.

The use of drugs that inhibit the secretion of hydrochloric acid in the stomach, including proton pump inhibitors, is accompanied by an increase in the content of the microbial flora in the stomach, normally present in the gastrointestinal tract.The use of proton pump inhibitors can lead to a slight increase in the risk of infectious diseases of the gastrointestinal tract caused by Salmonella spp., Campylobacter spp. and in hospitalized patients, probably, Clostridium difficile.

In children less than 1 month old and 1-11 months old, compared with oral esomeprazole 0.5 mg / kg and 1.0 mg / kg, respectively, there was a decrease in the mean percentage of time with an intragastric pH value of less than 4. Profile safety of esomeprazole in children is similar to that of adults.

Pharmacokinetics:

Suction and distribution

The apparent volume of distribution in the equilibrium state in healthy people is approximately 0.22 l / kg body weight. Esomeprazole binds to plasma proteins by 97%.

Metabolism

Esomeprazole undergoes complete metabolism involving the cytochrome P450 system. The main part is metabolized with the participation of a specific polymorphic isoenzyme CYP2C19, thus formed hydroxylated and desmethylated metabolites of esomeprazole. The metabolism of the remainder is carried out by isoenzyme CYP3A4; In this case, the sulfo derivative of esomeprazole is formed, the main metabolite, which is determined in the blood plasma.

The parameters given below mainly reflect the nature of pharmacokinetics in patients with increased isoenzyme activity CYP2C19.

The total plasma clearance is approximately 17 l / h after a single administration of esomeprazole and 9 l / h - with repeated administration. The half-life (T1 / 2) is 1.3 hours with repeated administration of esomeprazole once a day. Area under the pharmacokinetic curve "concentration-time" (AUC) increases with repeated administration. This increase is time- and dose-dependent, which is the consequence of a decrease in metabolism during the "first passage" through the liver, as well as a decrease in systemic clearance, probably due to the fact that esomeprazole and / or its sulfo derivative inhibits the isoenzyme CYP2C19.

With repeated intravenous administration of esomeprazole at a dose of 40 mg, the average maximum plasma concentration is approximately 1.6 μmol / L. When administered in similar doses, the average maximum concentration in the blood plasma is 4.6 μmol / l. The total exposure (approximately 30%) is slightly less increased with intravenous esomeprazole compared with oral administration.With intravenous administration of esomeprazole at doses of 40 mg, 80 mg and 120 mg for 30 minutes followed by intravenous administration at a dose of 4 mg / h or 8 mg / h for 23.5 hours, a linear relationship AUC of the administered dose.

Excretion

With daily application once a day esomeprazole is completely excreted from the blood plasma during a break between administrations, there is no tendency to cumulate esomeprazole.

The main metabolites of esomeprazole do not affect the secretion of hydrochloric acid in the stomach. When administered orally, up to 80% of the dose of esomeprazole is excreted as metabolites by the kidneys, the other part by the intestine. In urine, less than 1% of esomeprazole is found in unchanged form.

Pharmacokinetics in selected patient groups

Patients with reduced isoenzyme activity CYP2C19

Approximately 2.9 ± 1.5% of the population has decreased isoenzyme activity CYP2C19. In such patients, the metabolism of esomeprazole is mainly carried out with the help of CYP3A4, and with repeated intake of esomeprazole in a dose of 40 mg once a day, the average AUC is 100% higher than in patients with increased isoenzyme activity CYP2C19.

Mean values of maximum plasma concentrations in patients with reduced isoenzyme activity were increased by approximately 60%.Similar differences were found with intravenous administration of esomeprazole. The noted features do not affect the dose and way of using esomeprazole.

Older and older patients

In elderly and older patients (71-80 years), the metabolism of esomeprazole does not change significantly.

Patients with hepatic impairment

In patients with impaired liver function of mild to moderate severity, esomeprazole metabolism may be impaired. In patients with impaired hepatic function, the metabolic rate is reduced, which leads to a doubling AUC for esomeprazole. Trends in the cumulation of esomeprazole and its major metabolites with the introduction of esomeprazole once a day is not observed.

Patients with impaired renal function

The study of pharmacokinetics in patients with impaired renal function was not performed. Because the kidneys exclude not the most esomeprazole, but its metabolites, it can be assumed that the metabolism of esomeprazole in patients with impaired renal function does not change.

Children

A study of the pharmacokinetics of esomeprazole in children aged 0 to 18 years was performed after a 3-minute intravenous injection once a day for 4 days.The maximum equilibrium concentration of esomeprazole in blood plasma (C_ss,max) were evaluated 5 minutes after the dose was administered in children in all age groups, and in adult patients - 7 minutes after dosing 40 mg and at the end of the infusion of 20 mg dose.

Table 1 presents the results of an evaluation of the systemic exposure of esomeprazole in the form of geometric averages (range).

Table 1

Age group	Dose	AUC, *μmol h / l**	Css, max, μmol / l
0-1 month *	0.5 mg / kg (n=6)	7,5 (4,5-20,5)	3,7 (2,7-5,8)
1-11 months *	1.0 mg / kg (n=6)	10,5 (4,5-22,2)	8,7 (4,5-14,0)
15 years	10 mg (n=7)	7,9 (2,9-16,6)	9,4 (4,4-17,2)
6-11 years old	10 mg (n=8)	6,9 (3,5-10,9)	5,6 (3,1-13,2)
6-11 years old	20 mg (n=8) 20 mg (n=6)**	14,4 (7,2-42,3) 10,1 (7,2-13,7)	8,8 (3,4-29,4) 8,1 (3,4-29,4)
12-17 years old	20 mg (n=6)	8,1 (4,7-15,9)	7,1 (4,8-9,0)
12-17 years old	40 mg (n=8)	17,6 (13,1-19,8)	10,5 (7,8-14,2)
Adults	20 mg (n=22)	5,1 (1,5-11,8)	3,9 (1,5-6,7)
Adults	40 mg (n=41)	12,6 (4,8-21,7)	8,5 (5,4-17,9)

* The age group from 0 to 1 month included patients with adjusted age (the amount of fetal age and age after birth in full weeks) ≥ 32 full weeks and <44 complete weeks. The age group from 1 to 11 months included patients with an adjusted age ≥ 44 full weeks.

** Two patients were excluded - one due to reduced isoenzyme activity CYP2C19, the second - in connection with the concomitant use of the inhibitor of isoenzyme CYP3A4.

According to the constructed model C_ss,max after intravenous administration of esomeprazole in the form of a 10-minute, 20-minute and 30-minute infusion will decrease, on average,by 37% - 49%, 54% - 66% and 61% - 72%, respectively, in all age groups and dosing groups compared to the value C_ss,max after a 3-minute injection.

Indications:

Adults

1. As an alternative to oral therapy when it is not possible to carry out:

- with gastroesophageal reflux disease in patients with esophagitis and / or severe symptoms of reflux disease;

- for the healing of peptic ulcers associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs);

- for the prevention of peptic ulcers associated with the administration of NSAIDs in patients at risk.

2. To prevent the recurrence of bleeding from the peptic ulcer after endoscopic hemostasis.

Children (aged 1 to 18 years)

1. As an alternative to oral therapy when it is not possible to conduct:

- with gastroesophageal reflux disease in patients with erosive reflux esophagitis and / or severe symptoms of reflux disease.

Contraindications:

- Hypersensitivity to esomeprazole, substituted benzimidazoles or other ingredients of the drug;

- children's age under 1 year and children's age under 18 years for other indications, except gastroesophageal reflux disease;

- Esomeprazole should not be taken together with atazanavir and nelfinavir (see p.section "Interaction with other drugs and other forms of interaction").

Carefully:

A drug Esomeprazole-native should be used with caution in patients with severe renal insufficiency.

Pregnancy and lactation:

Currently, data on the use of esomeprazole during pregnancy are limited. In animal studies, there was no direct or indirect adverse effect of esomeprazole on the development of the embryo or fetus. The introduction of the racemic mixture of esomeprazole also did not have any negative impact on animals during pregnancy, childbirth, and postnatal development.

Assign esomeprazole during pregnancy should be only when the expected benefit for the mother exceeds the possible risk to the fetus.

There is no data on the use of esomeprazole in women during breastfeeding. It is not known whether esomeprazole with breast milk, so you should not prescribe esomeprazole in the period of breastfeeding. If esomeprazole therapy is necessary during breastfeeding, consideration should be given to stopping breastfeeding.

Dosing and Administration:

Adults

As an alternative to oral therapy when it is not possible

If oral therapy can not be administered to patients, the drug may be recommended Esomeprazole-native parenterally in a dose of 20-40 mg once a day.

1. When gastroesophageal reflux disease in patients with esophagitis is recommended esomeprazole in a dose of 40 mg once a day. For the treatment of GERD symptoms esomeprazole is used in a dose of 20 mg once a day.

2. For the healing of peptic ulcers associated with the administration of NSAIDs in patients at risk, it is recommended that esomeprazole in a dose of 20 mg once a day.

3. For the prevention of peptic ulcers associated with the administration of NSAIDs, it is recommended that esomeprazole in a dose of 20 mg once a day.

Typically, the period of treatment with intravenous form is short, the patient should be transferred to oral esomeprazole as soon as possible.

To prevent the recurrence of bleeding from the peptic ulcer after endoscopic hemostasis

After endoscopic hemostasis is recommended esomeprazole in a dose of 80 mg in the form of an intravenous infusion for 30 minutes followed by a prolonged intravenous infusion of esomeprazole at a dose of 8 mg / h for 3 days (72 hours).After the completion of parenteral therapy to suppress the secretion of hydrochloric acid, antisecretory therapy is recommended (for example, esomeprazole 40 mg once a day for 4 weeks).

Injections

A dose of 40 mg

A prepared solution of esomeprazole (5 ml, 8 mg / ml) is administered intravenously for at least 3 minutes.

A dose of 20 mg

Half of the prepared solution of esomeprazole (2.5 ml, 8 mg / ml) is administered intravenously for at least 3 minutes. Unused solution residues must be disposed of.

Infusion

A dose of 40 mg

The prepared esomeprazole solution is administered as an intravenous infusion for 10-30 minutes.

A dose of 20 mg

Half of the prepared solution of esomeprazole is administered as an intravenous infusion for 10-30 minutes. Unused solution residues must be disposed of.

A dose of 80 mg

The prepared esomeprazole solution is administered as an intravenous infusion for 30 minutes.

A dose of 8 mg / h

The prepared esomeprazole solution is administered as an extended intravenous infusion for 71.5 hours (8 mg / h). The conditions and the shelf life of the prepared solution, see "Preparing the solution".

Children (aged 1 to 18 years)

As an alternative to oral therapy when it is not possible

- With gastroesophageal reflux disease in patients with erosive reflux esophagitis and / or severe symptoms of reflux disease - esomeprazole parenterally once a day, as part of a course of GERD therapy (recommendations for dosing are presented in Table 2).

Typically, the period of treatment with the intravenous form should be short, the patient should be transferred to oral esomeprazole as soon as possible.

Recommendations for dosage of esomeprazole in children

Age

Treatment of erosive reflux esophagitis

Symptomatic treatment of GERD

1-11 years old

Body weight less than 20 kg:

10 mg once a day

Body weight 20 kg and more:

10 mg or 20 mg once daily

10 mg once a day

12-17 years old

40 mg once a day

20 mg once a day

Injections

A dose of 40 mg

A prepared solution of esomeprazole (5 ml, 8 mg / ml) is administered intravenously for at least 3 minutes.

A dose of 20 mg

Half of the prepared solution of esomeprazole (2.5 ml, 8 mg / ml) is administered intravenously for at least 3 minutes. Unused solution residues must be disposed of.

A dose of 10 mg

A quarter of the prepared solution of esomeprazole (1.25 ml, 8 mg / ml) is administered intravenously for at least 3 minutes.Unused solution residues must be disposed of.

Infusion

A dose of 40 mg

A prepared solution of esomeprazole (5 ml, 8 mg / ml) is administered as an intravenous infusion for 10-30 minutes.

A dose of 20 mg

Half of the prepared solution of esomeprazole (2.5 ml, 8 mg / ml) is administered as an intravenous infusion for 10-30 minutes. Unused solution residues must be disposed of.

A dose of 10 mg

A quarter of the prepared esomeprazole solution (1.25 ml, 8 mg / ml) is administered as an intravenous infusion for 10-30 minutes. Unused solution residues must be disposed of.

The conditions and the shelf life of the prepared solution, see "Preparing the solution".

Patients with impaired renal function

Correction of the dose of esomeprazole in patients with impaired renal function is not required. Due to the limited experience with esomeprazole in patients with severe renal insufficiency, caution should be exercised in the treatment of such patients (see section "Pharmacokinetics").

Patients with hepatic impairment

GERD: correction of the dose of esomeprazole in patients with impaired liver function of mild and moderate severity is not required.In patients with impaired hepatic function, the maximum daily dose is 20 mg (see the section "Pharmacokinetics").

Bleeding from the peptic ulcer: dose adjustment of esomeprazole in patients with impaired liver function of mild to moderate severity is not required.

In patients with impaired hepatic function, the following regimen for the administration of esomeprazole is recommended: 80 mg in the form of an intravenous infusion for 30 minutes followed by an extended intravenous infusion at a maximum dose of 4 mg / h for 71.5 hours (see Pharmacokinetics section) .

Older and older patients

Correction of the dose of esomeprazole in patients of the elderly and older is not required.

Preparation of the solution

The degradation of the prepared solution mainly depends on the pH value, and therefore only 0.9% sodium chloride solution for intravenous administration should be used to dissolve the drug.

The prepared solution should not be mixed or administered together with other drugs.

Before use, the solution should be assessed visually for no visible mechanical impurities and discoloration.Only a clear solution can be used. The prepared solution is recommended to enter immediately after preparation (from the microbiological point of view).

The prepared solution should be used within 12 hours. Store at a temperature not exceeding 30 ° C.

Unused residue should be disposed of in accordance with local regulations.

Injection 40 mg

Solution for injection (8 mg / ml) is prepared by adding 5 ml of 0.9% sodium solution chloride for intravenous administration into a vial of 40 mg esomeprazole. Diluted a solution of esomeprazole is a clear liquid from colorless to pale yellow.

Infusion 40 mg

The infusion solution is prepared by dissolving the contents of one vial with 40 mg of esomeprazole in 100 ml of a 0.9% solution of sodium chloride for intravenous administration.

Infusion 80 mg

Infusion solution is prepared by dissolving the contents of two flasks with esomeprazole 40 mg in 100 ml of 0.9% sodium chloride solution for intravenous administration. The diluted esomeprazole solution is a clear liquid from colorless to pale yellow.

Side effects:

Below are the undesirable reactions noted with intravenous and oral administration of esomeprazole.

The undesirable reactions presented below are listed in accordance with the damage to organs and organ systems. The incidence of undesirable reactions is estimated as follows: "very often" arising -> 10%; "often" -> 1% and <10%, "infrequently" -> 0.1% and <1%, "rarely" -> 0.01% and <0.1%, "very rarely" - <0, 01%, including individual messages.

Disturbances from the blood and lymphatic system: rarely - Lakopenia, thrombocytopenia; rarely - agranolocytosis, pancytopenia.

Immune system disorders: rarely - hypersensitivity reactions (eg, fever, angioedema, anaphylactic reaction / anaphylactic shock).

Disorders from the metabolism and nutrition: infrequently - peripheral edema; rarely - hyponatremia; rarely - hypomagnesemia, hypocalcemia due to severe hypomagnesemia, hypokalemia due to hypomagnesemia.

Disorders of the psyche: infrequently - Insomnia; rarely - Depression, agitation, confusion; rarely hallucinations, aggressive behavior.

Disorders from the nervous system: often - headache; infrequently - dizziness, paresthesia, drowsiness; rarely - a taste disorder.

Disorders from the side of the organ of vision: rarely blurred vision.

Disturbances from the respiratory, thoracic and mediastinal systems: rarely - bronchospasm.

Disorders from the gastrointestinal tract: often - abdominal pain, constipation, diarrhea, flatulence, nausea / vomiting; infrequently - dry mouth; rarely - stomatitis, candidiasis of the gastrointestinal tract; rarely - microscopic colitis (confirmed histologically).

Disorders from the liver and bile ducts: infrequently - increased activity of "liver" enzymes; rarely - Hepatitis (with jaundice or without); rarely - hepatic insufficiency, encephalopathy in patients with liver disease.

Disorders from the rut and subcutaneous tissues: often - reactions at the injection site *; infrequently - dermatitis, itching, rashes, hives; rarely - alopecia, photosensitivity; rarely - multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Disturbances from musculoskeletal and connective tissue: rarely - arthralgia, myalgia; rarely - Muscular weakness.

Disorders from the kidneys and urinary tract: very rare interstitial nephritis.

Violations of the genitals and the breast: very rare - gynecomastia.

General disorders and disorders at the site of administration: rarely - malaise, sweating.

* Reactions at the site of administration of esomeprazole, mainly observed in a clinical study with the appointment of esomeprazole in a high dose for 3 days (72 hours). In the pre-clinical study of esomeprazole, there was no irritant effect for intravenous administration, but a weak inflammatory response was observed with subcutaneous administration of esomeprazole, depending on the concentration of esomeprazole.

Individual cases of irreversible visual impairment with intravenous administration of omeprazole in critical patients have been reported, especially when high doses have been administered, a cause-and-effect relationship with omeprazole has not been established.

Data on the safety of esomeprazole in children are consistent with the safety profile in adults.

If any of the unwanted reactions listed in the manual is aggravated or you notice any other undesirable reactions not listed in the instructions, inform the doctor about it.

Overdose:

Symptoms

At the moment, very rare cases of deliberate overdose are described. With oral administration of esomeprazole at a dose of 280 mg, weakness and symptoms with side of the gastrointestinal tract. A single dose of esomeprazole at a dose of 80 mg by mouth and an intravenous dose of 308 mg for 24 hours did not cause any negative consequences.

Treatment

The antidote of esomeprazole is unknown. Esomeprazole binds well to plasma proteins, so dialysis is ineffective. In case of an overdose, it is necessary to carry out symptomatic and general supportive treatment.

Interaction:

Studies on the study of interactions were conducted only with the participation of adult patients.

Effect of esomeprazole on the pharmacokinetics of other drugs

Decrease in secretion of hydrochloric acid in the stomach during the treatment with esomeprazole and other inhibitors of the proton pump can lead to a decrease or increase in the absorption of other drugs, the absorption of which depends on the acidity of the medium. Like other drugs that reduce the acidity of gastric juice,treatment with esomeprazole may lead to a decrease in absorption of ketoconazole, itraconazole and erlotinib, as well as an increase in the absorption of such drugs as digoxin. Joint reception of omeprazole at a dose of 20 mg once a day and digoxin increases the bioavailability of digoxin by 10% (bioavailability of digoxin was increased by up to 30% in 20% of patients).

It was shown that omeprazole interacts with some antiretroviral drugs. The mechanisms and the clinical significance of these interactions are not always known. An increase in pH on the background of omeprazole therapy may affect the absorption of antiretroviral drugs. It is also possible to interact at the isoenzyme level CYP2C19. In the joint use of omeprazole and certain antiretroviral drugs, such as atazanavir and nelfinavir, against the background of omeprazole therapy, there is a decrease in their concentration in the blood plasma. Therefore, their simultaneous application is not recommended. The combined use of omeprazole (40 mg once daily) with atazanavir 300 mg / ritonavir 100 mg by healthy volunteers resulted in a significant decrease in the bioavailability of atazanavir (AUC, the maximum (C_m_Oh) and the minimum (C_min) concentrations decreased by approximately 75%).An increase in the dose of atazanavir by 400 mg did not compensate for the effects of omeprazole on the bioavailability of atazanavir.

With the simultaneous use of omeprazole and saquinavir, an increase in the concentration of saquinavir in the blood plasma was noted, when used with some other antiretroviral drugs, their concentration did not change. Given the similar pharmacokinetic and pharmacodynamic properties of omeprazole and esomeprazole, the combined use of esomeprazole with antiretroviral drugs, such as atazanavir and nelfinavir, Not recommended. Esomeprazole inhibits CYP2C19 - the main isoenzyme involved in its metabolism. Joint use of esomeprazole with other drugs, in the metabolism of which takes part isoenzyme CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin and others, can lead to an increase in the concentrations of these drugs in the blood plasma and require a dose reduction. When oral intake of esomeprazole at a dose of 30 mg and diazepam by 45% decreases the clearance of diazepam, which is the substrate of the isoenzyme CYP2C19.

When co-administered at an oral dose of esomeprazole and 40 mg of phenytoin in patients with epilepsy 13% increased residual concentration of phenytoin in blood plasma. In this regard, it is recommended to control the concentration of phenytoin in the blood plasma at the beginning of treatment with esomeprazole and when it is withdrawn.

The use of omeprazole in a dose of 40 mg once a day led to an increase AUC and C_m_Oh voriconazole (substrate isoenzyme CYP2C19) by 15% and 41% respectively.

When using esomeprazole orally in a dose of 40 mg by patients receiving warfarin, the coagulation time remained within the allowed values. However, several cases of a clinically significant increase in the international normalized ratio (INR) have been reported in the combined use of warfarin and esomeprazole. In this regard, monitoring of INRs at the beginning and after the end of the joint use of these drugs is recommended.

According to the research mentioned pharmacokinetic / pharmacodynamic interaction between clopidogrel (300 mg loading dose and maintenance dose of 75 mg / day), and esomeprazole (40 mg / day orally), which leads to a decrease in the exposure of the active metaboliteclopidogrel an average of 40% and a decrease in the maximum inhibition of ADP-induced platelet aggregation by an average of 14 %.

The clinical significance of this interaction is not clear. In a prospective study in patients receiving placebo or omeprazole in a dose of 20 mg per day, simultaneously with clopidogrel and acetylsalicylic acid (ASA) therapy, and in the analysis the clinical outcomes of large-scale, randomized trials have not been shown to increase the risk of cardiovascular complications when combined with clopidogrel and proton pump inhibitors, including esomeprazole.

The results of a number of observational studies are contradictory and do not give an unambiguous answer about the presence or absence of an increased risk of thromboembolic cardiovascular complications against the background of joint use of clopidogrel and proton pump inhibitors.

When clopidogrel was used together with a fixed combination of 20 mg of esomeprazole and 81 mg of ASA, the exposure of the active metabolite of clopidogrel decreased by almost 40% compared to clopidogrel alone, with the maximum levels of inhibition of ADP-induced platelet aggregation being the same, probably due to simultaneous administration ASA in a low dose.

The use of omeprazole at a dose of 40 mg once a day led to an increase in C_m_Oh and AUC of cystostaxol by 18% and 26%, respectively; for one of the active metabolites of cilostazol, the increase was 29% and 69%, respectively.

In healthy volunteers, a combined oral intake of esomeprazole 40 mg and cisapride 32% increased the value AUC and increased by 31% T_1/2 for cisapride; FROM_m_Oh cisapride in the blood plasma at the same time did not change significantly. Slight lengthening of the interval QT, which was observed with monotherapy with cisapride, did not increase with addition of esomeprazole (see section "Special instructions").

With simultaneous use of esomeprazole and tacrolimus, tacrolimus concentration in the blood plasma increased.

Some patients reported increased concentrations of methotrexate against a background of combined use with proton pump inhibitors. When prescribing high doses of methotrexate, the possibility of temporary withdrawal of esomeprazole should be considered. Shown, that esomeprazole does not cause clinically significant changes in the pharmacokinetics of amoxicillin and quinidine.

Studies on the study of the interaction of esomeprazole with otherdrugs with its intravenous use in high doses (80 mg followed by a dose of 8 mg / h) was not performed. Perhaps, with this dosing regime esomeprazole has a more pronounced effect on the pharmacokinetics of isoenzyme substrates CYP2C19. Therefore, patients should be under close medical supervision during intravenous administration of esomeprazole.

The effect of drugs on the pharmacokinetics of esomeprazole

In the metabolism of esomeprazole, isozymes participate CYP2C19 and CYP3A4. Joint oral administration of esomeprazole and an isoenzyme inhibitor CYP3A4, clarithromycin (500 mg twice a day) leads to a twofold increase in the value AUC for esomeprazole. Joint use of esomeprazole and a combined inhibitor of isoenzymes CYP3A4 and CYP2C19, for example, voriconazole, can lead to more than a twofold increase in the value AUC for esomeprazole. As a rule, in such cases, dosage correction of esomeprazole is not required. Correction of the dose of esomeprazole may be required in patients with impaired hepatic function and with prolonged use.

Medicines inducing isoenzymes CYP2C19 and CYP3A4, such as rifampicin and medicinal products of St. John's wort, when administered together with esomeprazole, can lead to a decrease in the concentration of esomeprazole in the blood plasma by accelerating the metabolism of esomeprazole.

To dissolve the drug Esomeprazole-native Only the medicinal products mentioned in the section "Preparation of the solution" should be used.

Special instructions:

In the presence of any anxiety symptoms (for example, such as significant spontaneous weight loss, recurrent vomiting, dysphagia, vomiting with blood or melena), and if there is a stomach ulcer (or suspected gastric ulcer), the presence of a malignant tumor should be excluded because drug treatment Esomeprazole-native can lead to a smoothing of the symptoms and delay the diagnosis.

In rare cases, patients who have been taking long-term omeprazole, histological examination of biopsy specimens of the mucous membrane of the body of the stomach revealed atrophic gastritis.

Effect on the ability to drive transp. cf. and fur:

Due to the fact that during therapy with the drug Esomeprazole-native dizziness, blurred vision and drowsiness may occur, caution should be exercised when driving vehicles and mechanisms, as well as when engaging in other potentially hazardous activities requiring increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Lyophilizate for the preparation of a solution for intravenous administration, 40 mg.

Packaging:

Lyophilizate, containing 40 mg of esomeprazole, in bottles of colorless glass of the first hydrolytic class, hermetically sealed with rubber stoppers covered with aluminum-plastic caps.

The labels are glued on the vials.

10 bottles along with the instructions for use are placed in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004232

Date of registration:05.04.2017

Expiration Date:05.04.2022

The owner of the registration certificate:NATIVA, LLC NATIVA, LLC Russia

Manufacturer: & nbsp

NATIVA, LLC Russia

Information update date: & nbsp17.05.2017

Illustrated instructions

Instructions

Esomeprazole-native (Ezomeprazole-nativ)