Instruction for use: Esomeprazol (Esomeprazolum)

Characteristic of Ademetionin

Proton pump inhibitors

Nosological classification (ICD-10)

K21 Gastroesophageal reflux

Biliary reflux esophagitis, gastrocardiac syndrome, Gastroesophageal reflux disease, Gastro-oesophageal reflux disease, Non-erosive reflux disease, syndrome gastrocardiac, Remhelda syndrome, Erosive reflux esophagitis, Ulcerative reflux esophagitis

K21.0 Gastro-oesophageal reflux with oesophagitis

Reflux gastritis, Reflux esophagitis, Erosive and ulcerative esophagitis

K25 Gastric ulcer

Helicobacter pylori, Pain syndrome in gastric ulcer, Pain syndrome in gastric ulcer and duodenal ulcer, Inflammation of the gastric mucosa, Inflammation of the gastrointestinal mucosa, Benign gastric ulcer, The disease of the stomach and duodenum, asotsiirovannoe with Helicobacter pylori, Aggravation gastroduodenita on the background of peptic ulcer, Exacerbation of peptic ulcer, The aggravation of gastric ulcer, The organic gastrointestinal disease, Peptic ulcer of the stomach and duodenum, Postoperative gastric ulcer, Recurrent ulcers, Symptomatic gastric ulcers, Chronic inflammatory disease of the upper gastrointestinal tract, associated with Helicobacter pylori, Helicobacter pylori eradication, Erosive and ulcerative lesions of the stomach, Erosive lesions of the stomach, The erosion of the gastric mucosa, Peptic ulcer disease, Stomach ulcer, Gastric lesion, Ulcerative lesions of the stomach, Symptomatic ulcers of the stomach and duodenum

K26 Duodenal Ulcer

Pain with duodenal ulcer, Pain syndrome in gastric ulcer and duodenal ulcer, The disease of the stomach and duodenum, asotsiirovannoe with Helicobacter pylori, Exacerbation of peptic ulcer, The worsening of duodenal ulcer, Peptic ulcer of the stomach and duodenum, Relapse of duodenal ulcers, Symptomatic ulcers of the stomach and duodenum, Helicobacter pylori eradication, Erosive and ulcerative lesions of the duodenum, Erosive-ulcerative lesions of duodenal ulcers associated with Helicobacter pylori, Erosive lesions of the duodenum, Duodenal ulcer, Ulcerative lesions of the duodenum]

K27 Peptic ulcer, unspecified

Perforation of peptic ulcer, Drug-induced gastrointestinal ulcers, medication ulcers, Peptic ulcer of the digestive tract, Peptic ulcer with Helicobacter pylori, peptic ulcer, Damage of gastrointestinal mucosa caused by NSAID, Symptomatic ulcers digestive tract, stress ulcer, Stress gastric ulcer, Stress damage to the mucous membrane, stress ulcer, duodenal ulcer Stress, Stress ulcer, Stressful GI ulcers, Erosive-ulcerative lesions of the gastrointestinal tract, The erosion of the gastrointestinal tract, Erosion of the mucosa of the upper gastrointestinal tract, The erosion of the gastrointestinal mucosa, gastrointestinal ulcer, ulcer drug, peptic ulcer, postoperative ulcer, stress ulcer, Ulcerative lesions of the gastrointestinal tract, Acute stress ulcer gastrointestinal tract, Symptomatic gastrointestinal ulcers, Complications of peptic ulcers

K31.8.2 * Hyperacidity of gastric juice

Pathological hypersecretion, Hyperacid indigestion, Hyperadic states, Increased secretion of gastric juice, Increased acid formation, Hyperacidosis,Hyper secretion of gastric juice, Increased acidity of gastric juice, High acidity

K86.8.3 * Zollinger-Ellison Syndrome

Adenoma of the pancreas ulzerogennosti, gastrinoma, Zollinger-Ellison Syndrome, gastrinoma

Y45 adverse reactions in therapeutic use of analgesic, antipyretic and anti-inflammatory agents

Code CAS 119141-88-7

Characteristic substance Esomeprazole

S-isomer of omeprazole.

Pharmacology

Pharmacological action - inhibiting proton pump.

Pharmacodynamics

Reduces the secretion of hydrochloric acid in the stomach due to specific target mechanisms of action. It is a specific proton pump inhibitor in the parietal cells of the gastric mucosa. S-isomer and R-isomer of omeprazole have similar pharmacodynamic activity.

Localization and mechanism of action

Esomeprazole is a weak base, it concentrates and becomes active in the strongly acidic environment of the secretory tubules of the parietal cells, where it inhibits the proton pump - the enzyme H + / K + -ATPase. Esomeprazole inhibits both basal and stimulated gastric secretion.

Effect on gastric acid secretion

After ingestion of esomeprazole orally at a dose of 20 or 40 mg, the therapeutic effect develops within 1 hour. When taken daily for 5 days, 20 mg 1 time per day, the average maximum release of hydrochloric acid after stimulation with pentagastrin is reduced by 90% when measured after 6-7 hours after taking the dose on the 5th day of treatment.

In patients with symptomatic GERD, after 5 days orally taking esomeprazole orally at a dose of 20 or 40 mg, the pH in the stomach was maintained at> 4 for an average of 13 and 17 hours per day, respectively. With the use of esomeprazole at a dose of 20 mg / day, maintaining pH in the stomach at> 4 for 8, 12 and 16 h was achieved in 76, 54 and 24% of patients, respectively. When using esomeprazole at a dose of 40 mg / day, this ratio was 97, 92 and 56%, respectively.

Against the background of intravenous injection of 80 mg of esomeprazole for 30 minutes, followed by a prolonged intravenous infusion at a dose of 8 mg / h for 23.5 hours, the gastric pH was> 4 for an average of 21 hours and> 6 for 11–13 pm

There is a correlation between the concentration of esomeprazole in the blood plasma and the inhibition of the secretion of hydrochloric acid (the parameter AUC was used to estimate the concentration).

Therapeutic effect of reducing acidity

With the use of esomeprazole in a dose of 40 mg / day, the cure of reflux esophagitis occurs in approximately 78% of patients after 4 weeks of treatment and in 93% of patients after 8 weeks of treatment.

Treatment with esomeprazole at a dose of 20 mg 2 times a day in combination with appropriate antibiotics for 1 week resulted in successful eradication of H. pylori in approximately 90% of patients.

Patients with uncomplicated duodenal ulcer after a week-long course of eradication treatment do not require subsequent monotherapy with antisecretory agents for effective treatment of the ulcer and elimination of symptoms.

The efficacy of esomeprazole in bleeding from peptic ulcers was shown in a study in patients with bleeding endoscopically confirmed.

Other effects of reducing acidity

During treatment with antisecretory agents, the content of gastrin in the blood plasma increases as a result of a decrease in acid secretion. Due to the decrease in gastric acidity, the level of chromogranin A (CgA) also increases. Increasing the CgA concentration may influence the results of the examination when neuroendocrine tumors are detected. To prevent this, it is necessary to temporarily stop the use of esomeprazole 5 days before the examination.

It is possible that the increase in the number of enterochromaffin-like cells is associated with an increase in serum gastrin concentration, which is observed in some patients with prolonged treatment with esomeprazole.

In the course of long-term treatment with agents that lower the secretion of the gastric glands, there was a slight increase in the incidence of glandular cysts in the stomach. This is due to physiological changes as a result of marked inhibition of the secretion of hydrochloric acid. Cysts are benign in nature and undergo a reverse development. Reducing the acidity of gastric juice due to any drugs, including proton pump inhibitors, leads to an increase in the number of bacteria in the stomach (which are usually present in the gastrointestinal tract). Treatment with proton pump inhibitors can lead to a slight increase in the risk of gastrointestinal infections caused by Salmonella spp., Campylobacter spp. and probably Clostridium difficile in hospitalized patients.

In the course of two comparative studies conducted with ranitidine as an active reference drug, esomeprazole showed higher efficacy in treating peptic ulcers in patients who received NSAIDs, including selective COX-2 inhibitors.

Pharmacokinetics

Suction and distribution. Esomeprazole is unstable in an acidic environment, therefore, for oral use forms that are resistant to the action of gastric juice. In vivo, only a small fraction of esomeprazole is converted to the R-isomer. Esomeprazole is rapidly absorbed, Tmax is approximately 1-2 h after administration. Absolute bioavailability after a single dose of 40 mg is 64% and increases to 89% on the background of repeated administration 1 time per day. For a dose of 20 mg of esomeprazole, these figures are 50 and 68%, respectively. Vss in healthy volunteers is approximately 0.22 l / kg. Plasma protein binding - 97%. Eating slows down and reduces the absorption of esomeprazole in the stomach, but this does not have a significant effect on the effectiveness of inhibition of the secretion of hydrochloric acid.

When repeated in / in the introduction of esomeprazole at a dose of 40 mg, the average Cmax in plasma is approximately 13.6 μmol / l compared to 4.6 μmol / l when ingesting similar doses. The overall exposure is slightly less (approximately 30%) with IV injection of esomeprazole compared with oral administration.

Metabolism and excretion. Esomeprazole is completely metabolized with the participation of cytochrome P450 enzymes. The main part is metabolized with the participation of the polymorphic form of the CYP2C19 isoenzyme, with the formation of hydroxylated and desmethylated metabolites of esomeprazole. The rest of the esomeprazole is metabolized at the expense of another specific isoenzyme, CYP3A4, with the formation of a sulfo derivative of esomeprazole, which is the main metabolite detected in blood plasma. The parameters below reflect mainly the nature of pharmacokinetics in patients with increased activity of the isoenzyme CYP2C19.

Total plasma clearance is approximately 17 l / h after a single dose of the drug and 9 l / h after multiple doses. T1 / 2 of blood plasma is 1.3 hours with repeated use 1 time per day. The pharmacokinetics of esomeprazole was studied using a dose of 40 mg 2 times a day. AUC increased with repeated administration of esomeprazole. The dose-dependent increase in AUC with repeated administration of esomeprazole is non-linear. This dependence on time and dose is a consequence of a decrease in the metabolism of esomeprazole 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 sulfone metabolite inhibit the CYP2C19 isoenzyme. With daily intake 1 time per day, esomeprazole is completely removed from the blood plasma during the interval between doses and does not accumulate.

With the on / in the introduction of esomeprazole in doses of 40, 80 and 120 mg for 30 minutes, followed by a / in the introduction of a dose of 4 or 8 mg / h for 23.5 hours, a linear dependence of AUC on the administered dose was shown.

The major metabolites of esomeprazole do not affect the secretion of gastric acid. When ingested up to 80% of the dose is excreted in the form of metabolites by the kidneys, the rest is through the intestines. Less than 1% of unchanged esomeprazole is found in the urine.

Special patient groups.

Reduced activity of the isoenzyme CYP2C19. Approximately (2.9 ± 1.5)% of the population has decreased CYP2C19 isoenzyme activity. In such patients, the metabolism of esomeprazole is mainly carried out using the CYP3A4 isoenzyme. When systematically receiving 40 mg of esomeprazole 1 time per day, the average AUC value is 100% higher than the value of this parameter in patients with increased activity of the CYP2C19 isoenzyme. Mean plasma Cmax values in patients with reduced isoenzyme activity are increased by approximately 60%. Similar differences were found in the on / in the introduction of esomeprazole. These features do not affect the dose and method of application of esomeprazole.

Elderly age. In elderly patients (71–80 years), the metabolism of esomeprazole does not undergo significant changes.

Floor. After a single dose of 40 mg of esomeprazole, the average AUC value in women is 30% higher than in men. With daily intake 1 time per day, differences in pharmacokinetics in men and women are not observed. These features do not affect the dose and method of application of esomeprazole.

Liver dysfunction. In patients with mild and moderate liver failure, the metabolism of esomeprazole may be disturbed. In patients with severe hepatic insufficiency, the metabolic rate is reduced, which leads to an increase in the AUC value for esomeprazole by 2 times.

Impaired renal function. The study of pharmacokinetics in patients with renal insufficiency was not conducted. Since not the esomeprazole itself but its metabolites are eliminated through the kidneys, it can be assumed that the metabolism of esomeprazole does not change in patients with renal insufficiency.

Children and teenagers. In children and adolescents 12–18 years old after repeated administration of 20 and 40 mg of esomeprazole, the AUC and Tmax values in the blood plasma were similar to those in adults.

Use in GERD in children 1–11 years old. Healing of erosive esophagitis, confirmed by endoscopic data, was observed in 93.3% of patients aged 1-11 years after 8 weeks of therapy with esomeprazole. Patients with a body weight of less than 20 kg took esomeprazole in a daily dose of 5 or 10 mg, and patients with a body weight of more than 20 kg received 10 or 20 mg.

In children aged 1–11 years after repeated administration of 10 mg of esomeprazole, the AUC value was similar to the AUC value in adolescents and adults when taking 20 mg of esomeprazole. After repeated administration of 20 mg of esomeprazole, the AUC value was 6–11 times higher than the AUC value in adolescents and adults while taking 20 mg of esomeprazole.

The pharmacokinetics of esomeprazole in children with a / in the introduction studied after a 3-minute injection 1 time per day for 4 days. AUC and maximum plasma Css were evaluated 5 minutes after administration in various age groups. The maximum Css in children 1–17 years old was on average higher than in adults, and varied from 5.6 to 10.5 µmol / l, depending on age and dose. According to the model, the maximum Css after intravenous infusion in the form of an infusion over 10, 20 and 30 minutes will decrease on average by 37–49, 54–66 and 61–72%, respectively, in all age groups and dosing groups compared to maximum Css after a 3-minute injection.

Use of Esomeprazol

Oral administration.

Gastroesophageal reflux disease (treatment of erosive reflux esophagitis, long-term supportive treatment after healing of erosive reflux esophagitis to prevent relapse, symptomatic treatment); gastric ulcer and duodenal ulcer (in combination therapy of duodenal ulcers associated with H. pylori; prevention of recurrence of peptic ulcers associated with H. pylori); long-term acid suppression therapy in patients who have undergone bleeding from peptic ulcers (after intravenous administration of drugs lowering the secretion of the gastric glands to prevent relapse); gastric ulcer caused by prolonged use of NSAIDs (treatment); gastric and duodenal ulcer caused by taking NSAIDs in patients at risk (prevention); Zollinger-Ellison syndrome or other conditions characterized by pathological hypersecretion of the gastric glands, including idiopathic hypersecretion.

In / in the introduction

Adults. As an alternative to oral therapy when it is impossible to carry out with gastroesophageal reflux disease in patients with esophagitis and / or severe symptoms of reflux disease; the healing of peptic ulcers associated with taking NSAIDs; prevention of peptic ulcers associated with taking NSAIDs, patients at risk; prevention of recurrence of bleeding from peptic ulcers after endoscopic hemostasis.

Children (from 1 year to 18 years). As an alternative to oral therapy when it is impossible to carry out with gastroesophageal reflux disease in patients with erosive reflux esophagitis and / or severe symptoms of reflux disease.

Contraindications

Oral administration

Hypersensitivity to esomeprazole, substituted benzimidazoles; joint reception with atazanavir and nelfinavir (see. "Interaction"); breastfeeding period; age up to 12 years (data on the efficacy and safety of use in this group of patients are not available); age up to 1 year or body weight less than 10 kg (data on the effectiveness and safety of use in this group of patients are not available); age 1–4 years for other indications, except for the treatment of erosive esophagitis and symptomatic treatment of GERD; 4–11 years of age according to other indications, except for treatment of erosive esophagitis and symptomatic treatment of GERD and treatment of duodenal ulcer associated with H. pylori, as part of combination therapy; age over 12 years for other indications, except GERD and treatment of duodenal ulcer associated with H. pylori, as part of combination therapy.

In / in the introduction

Hypersensitivity to esomeprazole, substituted benzimidazoles; combined use with atazanavir and nelfinavir (see. "Interaction"); age up to 1 year; age up to 18 years on other indications, except GERD.

Restrictions for use

Simultaneous use of digoxin (in elderly patients), clopidogrel (see. "Interaction"); the emergence of new symptoms on the part of the gastrointestinal tract or a recent change already existing; previous operations on the gastrointestinal tract (see "Precautions"); jaundice, severe liver dysfunction; severe renal impairment (experience limited); pregnancy.

pregnancy and lactation

Category of action on the fetus by the FDA - C.

Currently, there is not enough data on the use of esomeprazole during pregnancy.

With the introduction of esomeprazole animals did not reveal any direct or indirect negative impact on the development of the embryo or fetus and the impact on reproductive function. The introduction of the racemic agent also did not have any negative effect on animals during pregnancy, childbirth, and also during postnatal development.

Esomeprazole should be prescribed to pregnant women only when the expected benefit to the mother exceeds the potential risk to the fetus. A study of pregnant women (300–1000 outcomes of pregnancies) showed no malformations or fetal / neonatal esomeprazole toxicity.

The use of esomeprazole during breastfeeding is contraindicated. Currently, there are insufficient data on the effect of esomeprazole on newborns and young children.

The effect of esomeprazole on fertility in animal studies using racemic agents has not been identified.

Side Effects

The undesirable effects listed below, noted during oral and IV application of esomeprazole, are classified according to their frequency of development as follows: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000); the frequency is unknown (the frequency of occurrence of events cannot be determined on the basis of available data).

From the side of blood and lymphatic system: rarely - leukopenia, thrombocytopenia; very rarely - agranulocytosis, pancytopenia.

From the nervous system and sensory organs: often - headache; infrequently - insomnia, dizziness, paresthesias, drowsiness, blurred vision; rarely - agitation, confusion, depression; very rarely - aggression, hallucinations.

On the part of the digestive tract: often - abdominal pain, constipation, diarrhea, flatulence, nausea / vomiting; infrequently - dry mouth; rarely - a violation of taste, stomatitis, gastrointestinal candidiasis; frequency unknown - microscopic colitis (confirmed histologically).

On the part of the liver and biliary tract: infrequently - increased activity of hepatic transaminases; rarely, hepatitis with or without jaundice; very rarely - liver failure, encephalopathy in patients with a history of liver disease.

On the part of the respiratory system, organs of the chest and mediastinum: rarely - bronchospasm.

On the part of the skin and subcutaneous tissues: rarely - dermatitis, itching, rash, urticaria; rarely - alopecia, photosensitivity; very rarely - erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis; frequency unknown - subacute cutaneous lupus erythematosus.

From the musculoskeletal system and connective tissue: infrequently - fractures of the femoral neck, wrist bones, vertebrae; rarely - arthralgia, myalgia; very rarely - muscle weakness.

On the part of the kidneys and urinary tract: very rarely - interstitial nephritis, in some patients the development of renal failure was reported.

On the part of the genitals and mammary gland: very rarely - gynecomastia.

Immune system disorders: rarely, hypersensitivity reactions (such as fever, angioedema, and anaphylactic reaction / anaphylactic shock).

Metabolism and malnutrition: infrequently - peripheral edema; rarely, hyponatremia; very rarely, hypomagnesemia (may be associated with hypokalemia), severe hypomagnesemia (may correlate with hypocalcemia).

General disorders and disorders at the injection site: rarely - malaise, excessive sweating.

In addition for intravenous administration: often - reactions at the injection site (mainly observed in a clinical trial when prescribing esomeprazole in a high dose for 3 days (72 hours). In a preclinical study of esomeprazole for intravenous administration, no irritating effect was found, however, a mild inflammatory reaction was observed in the s / c administration, depending on the concentration of esomeprazole).

It was reported about individual cases of irreversible visual impairment with the on / in the introduction of omeprazole to patients in critical condition, especially with the introduction of high doses, a causal relationship with the use of esomeprazole has not been established.

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

Interaction

The study of the interaction of esomeprazole was conducted only in adult patients.

Effect of esomeprazole on the pharmacokinetics of other drugs

Reduced acidity in the stomach during treatment with esomeprazole may lead to a decrease or increase in the absorption of other drugs, the absorption of which depends on the acidity of the medium. As with the use of other hydrochloric acid secretion or antacid agents, treatment with esomeprazole may decrease the absorption of ketoconazole, itraconazole and erlotinib and increase the absorption of drugs such as digoxin.

The simultaneous use of esomeprazole and a combined inhibitor of CYP3A4 and CYP2C19 isoenzymes, for example, voriconazole, can lead to an increase in the AUC of esomeprazole to 280%. As a rule, in such cases, dose adjustment of esomeprazole is not required. Dose adjustment of esomeprazole may be required in patients with severely impaired liver function and with prolonged use.

Drugs that induce isoenzymes CYP2C19 and CYP3A4, such as rifampicin and Hypericum perforatum drugs, when used simultaneously with esomeprazole can lead to a decrease in the concentration of esomeprazole in the blood plasma due to the acceleration of its metabolism.

Overdose

To date, extremely rare cases of deliberate overdose have been described. Ingestion of esomeprazole orally at a dose of 280 mg was accompanied by general weakness and symptoms of the gastrointestinal tract. A single dose of 80 mg of esomeprazole orally and in / in the introduction of 308 mg for 24 hours did not cause any negative effects.

The antidote esomeprazole is unknown. Esomeprazole binds well to plasma proteins, so dialysis is ineffective. In case of overdose, symptomatic and general supportive treatment should be carried out.

Route of administration

Inside, in / in.

Precautions substances esomeprazole

If there are any disturbing symptoms (such as significant spontaneous weight loss, frequent vomiting, dysphagia, vomiting with blood or melena), as well as in the presence or suspicion of a stomach ulcer, the development of a malignant neoplasm should be excluded, since treatment with esomeprazole can lead to smoothing symptoms and thus delay the formulation of the correct diagnosis.

Mandatory consultation of a specialist is necessary in the following cases:

- in the presence of a history of gastric ulcers or operations on the gastrointestinal tract;

- during the continuous symptomatic treatment of dyspepsia or heartburn for 4 weeks or more;

- with the development of jaundice or severe liver disease;

- patients older than 55 years old when new symptoms appear on the part of the gastrointestinal tract or recently change existing ones

- if necessary, endoscopic procedures or urease breathing test (H. pylori determination).

Patients with recurrent symptoms of dyspepsia / heartburn or receiving esomeprazole for a long period (especially more than 1 year) should be under regular medical supervision. Esomeprazole is not recommended for a long time for prevention.

Hypomagnesemia. A severe form of hypomagnesemia was observed in patients treated with proton pump inhibitors, such as esomeprazole, for at least 3 months and in most cases during treatment for a year. There have been serious manifestations of hypomagnesemia, such as chronic fatigue, convulsions, delirium, convulsions, dizziness, and ventricular arrhythmia, but they may begin gradually and go unnoticed. In most patients, hypomagnesemia disappeared after additional magnesium intake and discontinuation of a proton pump inhibitor.

For patients who may require long-term treatment or already taking a proton pump inhibitor in conjunction with digoxin or drugs that may cause hypomagnesemia (for example, diuretics), physicians should consider measuring the concentration of magnesium before taking a proton pump inhibitor and periodically during treatment.

Fractures. The use of proton pump inhibitors, especially in large doses and for a prolonged period (> 1 year), can lead to a moderate increase in the risk of a hip fracture, carpal bones and vertebral bodies, especially in older people or with other known risk factors. Studies suggest that taking these drugs may increase the overall risk of fractures by 10–40%. To a certain extent, this increase in risk may be due to exposure to other factors. Patients at risk for osteoporosis should be treated in accordance with current clinical guidelines and take the required amount of vitamin D and calcium.

During treatment with proton pump inhibitors, the concentration of gastrin in the blood plasma increases as a result of reduced intragastric secretion of hydrochloric acid.

In patients taking a proton pump inhibitor for a long time, the formation of glandular cysts in the stomach is more often noted. These phenomena are due to physiological changes as a result of inhibition of the secretion of hydrochloric acid. The cysts are benign and reverse developed. Patients on a treatment regimen as needed should be instructed to contact their physician when symptoms change. Taking into account fluctuations in the concentration of esomeprazole in the blood plasma when prescribing it in a regimen of therapy as needed, the interaction of esomeprazole with other drugs should be considered (see "Interaction").

When prescribing esomeprazole for the eradication of H. pylori, consideration should be given to