Esomeprazole Canon enteric-Soluble tablets 20mg, 14pcs

Composition

1 enteric-soluble film-coated tablet contains:

Active ingredient:

Esomeprazole magnesium dihydrate 21.8 mg, in terms of esomeprazole 20 mg.

Auxiliary substances:

Low-substituted hyprolose (hydroxypropylcellulose) 14 mg;

Pre-gelatinized corn starch 37.2 mg;

Colloidal silicon dioxide 2 mg;

Mannitol 23 mg;

Sodium stearyl fumarate 2 mg;

Microcrystalline cellulose 140 mg

Pharmacological action

A means of reducing the secretion of gastric glands is a proton pump inhibitor.

Pharmacodynamics

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

Mechanism of action Esomeprazole is a weak base that converts to the active form in the highly acidic environment of the secretory tubules of the parietal cells of the gastric mucosa and inhibits the proton pump-the enzyme H+/K+ – ATPase, while inhibiting both basal and stimulated secretion of hydrochloric acid.

Effect on the secretion of hydrochloric acid in the stomach After oral use of 20 mg or 40 mg, the effect of esomeprazole develops within 1 hour. When taking the drug daily for 5 days at a dose of 20 mg once a day, the average maximum concentration of hydrochloric acid after stimulation with pentagastrin decreases by 90% (when measuring the acid concentration 6-7 hours after taking the drug on the 5th day of therapy). In patients with gastroesophageal reflux disease (GERD) and the presence of clinical symptoms after 5 days of daily oral use of esomeprazole at a dose of 20 mg or 40 mg, the intragastric pH value above 4.0 was maintained for an average of 13 and 17 hours out of 24 hours. When esomeprazole was administered at a dose of 20 mg per day, intragastric pH values above 4.0 were maintained for at least 8,12, and 16 hours in 76%,54%, and 24% of patients, respectively.

A correlation was found between the concentration of the drug in plasma and inhibition of hydrochloric acid secretion (the AUC parameter – area under the “concentration – time”curve was used to estimate the concentration.

Therapeutic effect achieved by inhibiting the secretion of hydrochloric acid When taking the drug at a dose of 40 mg, healing of reflux esophagitis occurs in approximately 78% of patients after 4 weeks of therapy and in 93% of patients after 6 weeks of therapy.

Treatment with esomeprazole 20 mg twice daily in combination with appropriate antibiotics for one week results in successful eradication of Helicobacter pylori in approximately 90% of patients. Patients with uncomplicated peptic ulcer disease after a week-long eradication course do not require subsequent monotherapy with drugs that lower the secretion of gastric glands to treat ulcers and eliminate symptoms. Esomeprazole has been shown to be effective in endoscopically confirmed peptic ulcer bleeding.

Other effects associated with inhibition of hydrochloric acid secretion During treatment with drugs that lower the secretion of gastric glands, the concentration of gastrin in 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) increases. Increasing the concentration of CgA may affect the results of examinations for the detection of neuroendocrine tumors. To prevent this effect, it is necessary to temporarily stop taking esomeprazole 5 days before the CgA concentration study.

In patients treated with esomeprazole for a long time, an increase in the number of enterochromaffin-like cells was observed, probably due to an increase in the concentration of gastrin in plasma.

Patients who take drugs that reduce the secretion of gastric glands for a long period of time, the formation of glandular cysts in the stomach is more common. These phenomena are caused by physiological changes as a result of pronounced inhibition of hydrochloric acid secretion. Cysts are benign and undergo reverse development. The use of drugs that suppress the secretion of hydrochloric acid in the stomach, including proton pump inhibitors, is accompanied by an increase in the content of microbial flora in the stomach, which is normally present in the gastrointestinal tract. The use of proton pump inhibitors may lead to a slight increase in the risk of infectious diseases of the gastrointestinal tract caused by bacteria of the genus Salmonella spp. and Campylibacter spp. and, probably, Clostridium difficile in hospitalized patients.

In two comparative studies conducted with ranitidine, esomeprazole showed better efficacy in the treatment of gastric ulcers in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors.

Pharmacokinetics

Absorption and distribution Esomeprazole is unstable in an acidic environment, so tablets coated with enteric coatings are used for oral use. In vivo, only a small fraction of esomeprazole is converted to the R-isomer. Food intake slows down and reduces the absorption of esomeprazole in the stomach, but this does not significantly affect the effectiveness of inhibiting the secretion of hydrochloric acid.

The drug is rapidly absorbed: the maximum concentration (Cmax) in plasma is reached 1-2 hours after use. The absolute bioavailability of esomeprazole after a single dose of 40 mg is 64% and increases to 89% against the background of daily intake once a day. For a 20 mg dose of esomeprazole, these values are 50% and 68%, respectively. The volume of distribution at steady-state concentration in healthy individuals is approximately 0.22 l / kg of body weight. Esomeprazole binds to plasma proteins by 97%.

Metabolism and excretion Esomeprazole is metabolized by cytochrome P450 isoenzymes. The main part is metabolized with the participation of a specific polymorphic isoenzyme CYP2C19, while hydroxylated and demethylated metabolites of esomeprazole are formed. The remaining part is metabolized by the CYP3A4 isoenzyme, and the esomeprazole sulfide derivative is formed, which is the main metabolite detected in plasma.

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

Total clearance is approximately 17 l / h after a single dose of the drug and 9 l / h after repeated use. The half-life (half-life) is 1.3 hours when taken systematically once a day. AUC increases with repeated use of esomeprazole. The dose-dependent increase in AUC with repeated use of esomeprazole is non-linear, which is a consequence of a decrease in metabolism during the” first pass ” through the liver, as well as a decrease in systemic clearance, probably caused by inhibition of the CYP2C19 isoenzyme by esomeprazole and/or its sulfide derivatives.

 When taken daily once a day, esomeprazole is completely eliminated from the blood plasma in the interval between doses and does not accumulate. 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 is excreted in the form of metabolites by the kidneys, the other part – by the intestines. Less than 1% of unchanged esomeprazole is detected in the urine.

Features of pharmacokinetics in some groups of patients Approximately 2.9±1.5% of the population has reduced activity of the CYP2C19 isoenzyme. In such patients, esomeprazole is mainly metabolized by the CYP3A4 isoenzyme. When esomeprazole is systematically administered 40 mg once a day, the average AUC value (100%) exceeds the value of this parameter in patients with increased activity of the CYP2C19 isoenzyme. The average values of maximum plasma concentrations in patients with reduced isoenzyme activity are increased by approximately 60%. These features do not affect the dose and method of use of esomeprazole. In elderly patients (71-80 years), the metabolism of esomeprazole does not undergo significant changes. After a single 40 mg dose of esomeprazole, the mean AUC in women is 30% higher than in men. When taking the drug daily once a day, there are no differences in pharmacokinetics in men and women. These features do not affect the dose and method of use of esomeprazole.

In patients with mild to moderate hepatic insufficiency, esomeprazole metabolism may be impaired. In patients with severe hepatic insufficiency, the metabolic rate is reduced, which leads to a 2-fold increase in the AUC value for esomeprazole.

Pharmacokinetics have not been studied in patients with renal insufficiency. Since it is not esomeprazole itself that is eliminated through the kidneys, but its metabolite, it can be assumed that the metabolism of esomeprazole in patients with renal insufficiency does not change.

In children aged 12-18 years after repeated use of 20 mg and 40 mg esomeprazole, the AUC value and time to reach maximum concentration (TMAX) in blood plasma were similar to the AUC and TMAX values in adults.

Indications

• Gastroesophageal reflux disease (GERD): treatment of erosive reflux esophagitis: long-term maintenance treatment after healing of erosive reflux esophagitis, prevention of relapses; symptomatic treatment of GERD.

• Peptic ulcer of the stomach and duodenum in combination therapy: treatment of duodenal ulcer associated with Helicobacter pylori; prevention of relapses of peptic ulcer associated with Helicobacter pylori.

• Long-term acid-suppressing therapy in patients who have suffered bleeding from a peptic ulcer (after intravenous use of drugs that reduce the secretion of gastric glands, to prevent relapse). Patients taking NSAIDs for a long time: treatment of stomach ulcers caused by NSAIDs; prevention of gastric and duodenal ulcers caused by NSAIDs in patients at risk.

• Zollinger-Ellison syndrome or other conditions characterized by abnormal hypersecretion of the gastric glands, including idiopathic hypersecretion.

Contraindications

• Hypersensitivity to esomeprazole, substituted benzimidazoles or other components of the drug;
• Children under 12 years of age (due to the lack of data on the effectiveness and safety of the drug in this group of patients);
• Children aged from 12 to 18 years for all indications, except for GERD;
• Concomitant use with atazanavir and nelfinavir.

With caution: Severe renal failure (limited experience).

Use during pregnancy and lactation Currently, there are insufficient data on the use of esomeprazole during pregnancy. The results of epidemiological studies of esomeprazole, which is a racemic mixture, showed no fetotoxic effect or fetal development disorders.

In animal studies, no direct or indirect negative effects on the development of the embryo or fetus were found, both with the introduction of esomeprazole and with the introduction of a racemic mixture. Prescribe the drug to pregnant women only if the expected benefit to the mother exceeds the potential risk to the fetus. It is not known whether esomeprazole is excreted in breast milk, so the drug should not be used during breastfeeding.

Side effects

World Health Organization (WHO) classification of side effects: very common – >1/10 prescriptions (>>10%), common – >>>1/100 to >>><1/10 prescriptions (>1% and <1/10 prescriptions (><10%), infrequent – >1/1000 to <10%), infrequent – ><1/100 prescriptions (>0.1% and <1/100 prescriptions (><1%), rare – >1/10000 to <1%), rare – ><1/1000 appointments (>0.01% and <1/1000 appointments (><0.1%), very rare – <1/10000 appointments ( In each group, undesirable effects are presented in decreasing order of severity. Nervous system disorders: often: headache; infrequently: drowsiness, insomnia, dizziness, paresthesia. rare: agitation, confusion, depression. ; very rare: aggressive behavior, hallucinations. Respiratory system disorders: rare: bronchospasm. Disorders of the digestive system: often: abdominal pain, diarrhea, flatulence, nausea, vomiting, constipation; infrequently: dry mouth, increased activity of “liver” enzymes. rare: stomatitis, candidiasis of the gastrointestinal tract( GIT), hepatitis (with or without jaundice); very rare: liver failure, hepatic encephalopathy in patients with a history of liver disease, microscopic colitis. Renal and urinary tract disorders: very rare: interstitial nephritis. Frequency unknown: renal failure. Reproductive system disorders: very rare: gynecomastia. Musculoskeletal disorders: rare: arthralgia, myalgia; very rare: muscle weakness; frequency unknown: fractures of the femoral neck, wrist bones, vertebrae. Skin disorders: infrequently: pruritus, rash, urticaria, dermatitis, peripheral edema; rarely: alopecia, photosensitization, malaise, excessive sweating; very rarely: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme. Hematopoietic disorders: rare: leukopenia, thrombocytopenia; very rare: agranulocytosis, pancytopenia. Sensory disorders: Infrequently: blurred vision; rarely: taste disorders. Allergic reactions: rarely: hypersensitivity reactions (e. g. fever, angioedema, anaphylactic reaction/anaphylactic shock). Laboratory and instrumental data: rare: hyponatremia; very rare: hypomagnesemia, hypocalcemia due to severe hypomagnesemia, hypokalemia due to severe hypomagnesemia.

Interaction

Effect of esomeprazole on the pharmacokinetics of other drugs

A decrease in the secretion of hydrochloric acid in the stomach during treatment with esomeprazole and other proton pump inhibitors may lead to a change in the absorption of drugs, the absorption of which depends on the I acidity of the medium. Similar to antacids and other drugs that reduce the acidity of gastric juice, the use of esomeprazole can lead to a decrease in the absorption of ketoconazole, itraconazole and erlotinib, and an increase in the absorption of drugs such as digoxin.

Concomitant use of esomeprazole at a dose of 20 mg once a day and digoxin increases the bioavailability of digoxin by 10% (digoxin bioavailability increased by up to 30% in two out of 10 patients).

Esomeprazole is known to interact with some antiretroviral drugs. The mechanisms and clinical significance of these interactions are not always known. An increase in the pH value during esomeprazole therapy may affect the absorption of antiretroviral drugs. Interaction at the level of the CYP2C19 isoenzyme is also possible.

When esomeprazole is co-administered with some antiretroviral drugs, such as atazanavir and nelfinavir, while esomeprazole is being used, their serum concentrations decrease. Therefore, their simultaneous use is not recommended.

Co-use of esomeprazole 40 mg once daily and atazanavir 300 mg / ritonavir 100 mg in healthy volunteers resulted in a significant reduction in the bioavailability of atazanavir (AUC, as well as maximum and minimum concentrations decreased by approximately 75%). Increasing the dose of atazanavir to 400 mg did not compensate for the effect of esomeprazole on the bioavailability of atazanavir.

When esomeprazole and saquinavir were co-administered, an increase in the serum concentration of saquinavir was observed; when used with some other antiretroviral drugs, their concentration did not change. Given the similar pharmacokinetic and pharmacodynamic properties of omeprazole and esomeprazole, co-use of esomeprazole with antiretroviral drugs such as-atazanavir and nelfinavir is not recommended.

Esomeprazole inhibits the CYP2C19 isoenzyme, the main enzyme involved in its metabolism. Accordingly, the combined use of esomeprazole with other drugs that are metabolized by the CYP2C19 isoenzyme, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., may lead to an increase in plasma concentrations of these drugs, which, in turn, may require dose reduction. This interaction is especially important to keep in mind when prescribing Esomeprazole Canon in the “if necessary” mode. Co-use of 30 mg of esomeprazole and diazepam, which is a substrate of the CYP2C19 isoenzyme, resulted in a 45% decrease in the clearance of diazepam.

use of esomeprazole at a dose of 40 mg resulted in a 13% increase in the residual concentration of phenytoin in patients with epilepsy. In this regard, it is recommended to monitor the concentration of phenytoin in plasma at the beginning of treatment with esomeprazole and when it is discontinued.

Concomitant use of esomeprazole at a dose of 40 mg leads to an increase in the concentration of phenytoin in blood plasma in patients with epilepsy by 13%.

It is recommended to monitor the concentration of phenytoin in blood plasma at the beginning of esomeprazole therapy and when it is discontinued. When using esomeprazole at a dose of 40 mg once a day, the AUC and TCmax of voriconazole (a substrate of the CYP2C19 isoenzyme) increases by 15% and 41%, respectively.

Co-use of warfarin and 40 mg esomeprazole does not change the coagulation time in patients taking warfarin for a long time. However, several cases of clinically significant increases in the MHO (International Normalized Ratio) index have been reported when warfarin and esomeprazole are co-administered. It is recommended to monitor MHO at the beginning and end of co-use of esomeprazole and warfarin or other coumarin derivatives.

Co-use of cisapride with 40 mg of esomeprazole resulted in an increase in the pharmacokinetic parameters of cisapride in healthy volunteers: AUC – by 18% and Half-life-by 26%, for one of the active metabolites of cytostazole, the increase was 29% and 69%, respectively. Concomitant use of esomeprazole at a dose of 40 mg with cisapride resulted in an increase in the pharmacokinetic parameters of cisapride in healthy volunteers: AUC by 32% and Half-life by 31%, but the Cmax did not change significantly.

The slight prolongation of the QT interval, which was observed with cisapride monotherapy, did not increase with the addition of esomeprazole. In some patients, an increase in the concentration of methotrexate in the blood serum was noted against the background of simultaneous use with proton pump inhibitors. When using high doses of methotrexate, temporary discontinuation of esomeprazole should be considered.

Esomeprazole does not cause clinically significant changes in the pharmacokinetics of amoxicillin and quinidine. Studies evaluating the short-term co-use of esomeprazole and naproxen or rofecoxib did not reveal a clinically significant pharmacokinetic interaction.

Concomitant short-term use of esomeprazole and naproxen or rofecoxib did not reveal a clinically significant pharmacokinetic interaction.

A clinical study examined the interaction of clopidogrel (300 mg loading dose, followed by 75 mg / day) with esomeprazole (80 mg) simultaneously, at the same time for 5 days. The activity of the thiol metabolite (active metabolite) of clopidogrel was reduced by 46% (day 1 of therapy) and 42% (day 5 of therapy) when taking clopidogrel and omeprazole at the same time. When clopidogrel and esomeprazole were administered at the same time, the average inhibition of platelet aggregation (IRA) was reduced by 47% (during 24 hours of therapy) and 30% (on day 5 of therapy).

According to the results of another study: esomeprazole when used with clopidogrel not simultaneously, at different times, does not have an inhibitory effect on the CYP2C19 isoenzyme. Studies have reported conflicting data on the clinical manifestations of interactions with clopidogrel in the cardiovascular system. When used concomitantly with tacrolimus, it is possible to increase the serum concentrations of tacrolimus.

Effect of medicinal products on the pharmacokinetics of esomeprazole The isoenzymes CYP2C19 and CYP3A4 are involved in the metabolism of esomeprazole. Co-use of esomeprazole with clarithromycin (500 mg twice daily), which inhibits the CYP3A4 isoenzyme, leads to a 2-fold increase in the AUC of esomeprazole. Concomitant use of esomeprazole and a combined inhibitor of the CYP3A4 and CYP2C19 isoenzymes, such as voriconazole, can lead to a more than 2-fold increase in the AUC value for esomeprazole. As a rule, in such cases, no dose adjustment of esomeprazole is required. Drugs that induce CYP2C19 and CYP3A4 isoenzymes, such as rifampicin and St. John’s wort, when used concomitantly with esomeprazole, can lead to a decrease in the concentration of esomeprazole in blood plasma due to the acceleration of esomeprazole metabolism.

How to take, course of use and dosage

Inside. The tablet should be swallowed whole, without chewing, with a sufficient amount of water. Adults and children from 12 years of age Gastroesophageal reflux disease Treatment of erosive reflux esophagitis: 40 mg once a day for 4 weeks. An additional 4-week course of treatment is recommended in cases where healing of esophagitis does not occur after the first course or symptoms persist. Long-term maintenance treatment after healing of erosive reflux esophagitis, prevention of relapses: 20 mg once a day. Symptomatic treatment of GERD: 20 mg once a day in patients without esophagitis. If after 4 weeks of treatment the symptoms do not disappear, an additional examination of the patient should be performed. After eliminating the symptoms, you can switch to the “if necessary” mode of taking the drug-20 mg once a day if symptoms resume. For patients taking NSAIDs who are at risk of developing gastric or duodenal ulcers, treatment in the “if necessary” mode is not recommended. Adult gastric and duodenal ulcer disease in combination therapy for Helicobacter pylori eradication:Treatment of Helicobacter pylori-associated duodenal ulcer:Esomeprazole Canon 20 mg, amoxicillin 1000 mg and clarithromycin 500 mg. All medications are taken 2 times a day for 1 week. Prevention of recurrent peptic ulcer associated with Helicobacter pylori:Esomeprazole Canon 20 mg, amoxicillin 1000 mg and clarithromycin 500 mg. All medications are taken 2 times a day for 1 week. Long-term acid-suppressing therapy in patients who have suffered bleeding from a peptic ulcer (after intravenous use of drugs that reduce the secretion of gastric glands, to prevent relapse): Esomeprazole Canon 40 mg 1 time a day for 4 weeks after intravenous use of drugs that reduce the secretion of gastric glands. Patients taking NSAIDs for a long time after a stomach ulcer caused by taking NSAIDs: Esomeprazole Canon 20 mg once a day; treatment duration 4-8 weeks. Prevention of stomach and duodenal ulcers caused by NSAIDs: Esomeprazole Canon 20 mg once a day. Conditions characterized by abnormal hypersecretion of the gastric glands, including Zollinger-Ellison syndrome and idiopathic hypersecretion: The recommended initial dose of Esomeprazole Canon is 40 mg 2 times a day. Further, the dose is selected individually, the duration of treatment is determined by the clinical picture of the disease. There is experience with the use of 80 to 160 mg of esomeprazole per day, if the drug is taken more than 80 mg per day, it is recommended to divide the required dose into 2 doses. Renal failure: no dose adjustment of Esomeprazole Canon is required. However, experience with esomeprazole in patients with severe renal insufficiency is limited, and therefore caution should be exercised when prescribing the drug to this category of patients. Hepatic insufficiency: no dose adjustment is required for mild to moderate hepatic insufficiency. For patients with severe hepatic insufficiency, the maximum daily dose should not exceed 20 mg. Elderly patients: no dose adjustment is required.

Overdose

Currently, cases of esomeprazole overdose are described extremely rarely. Oral use of esomeprazole at a dose of 280 mg was accompanied by general weakness and symptoms from the gastrointestinal tract.

A single dose of 80 mg of esomeprazole did not cause any negative consequences.

Treatment: No specific antidote is known. Hemodialysis is ineffective. In case of overdose, symptomatic and general maintenance therapy is recommended.

Special instructions

In the presence of any alarming symptoms (for example, such as significant spontaneous weight loss, repeated vomiting, dysphagia, vomiting with blood or melena), as well as in the presence of a stomach ulcer (or if a stomach ulcer is suspected), the presence of a malignant neoplasm should be excluded, since treatment with esomeprazole may smooth out the symptoms and delay the diagnosis.

Patients taking the drug for a long period of time (especially more than a year) should be under regular medical supervision.

Patients taking esomeprazole “if necessary” should be instructed to contact their doctor if the nature of symptoms changes. Taking into account fluctuations in the concentration of esomeprazole in plasma when prescribing therapy “if necessary”, it is necessary to take into account the interaction of the drug with other drugs (see the section “Interaction with other drugs and other types of drug interaction”). When using esomeprazole for eradication of Helicobacter pylori, the possibility of drug interactions for all components of triple therapy should be taken into account.

Clarithromycin is a potent inhibitor of the CYP3A4 isoenzyme, so when using eradication therapy in patients receiving other drugs that are metabolized with the participation of the CYP3A4 isoenzyme (for example, cisapride), it is necessary to take into account possible contraindications and interactions of clarithromycin with these drugs. When using proton pump inhibitors, especially when they are used in large doses and for a long period (more than 1 year), there is a risk of fractures of the femoral neck, wrist bones and vertebrae (especially in elderly patients). There is also the formation of glandular cysts in the stomach, a decrease in the absorption of vitamin B12, and the development of hypomagnesemia.

Influence on the ability to drive vehicles and mechanisms

During the treatment period, dizziness, blurred vision and drowsiness may occur, so caution should be exercised when driving vehicles and engaging in other potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions.

Form of production

Round, biconvex tablets, film-coated from light green to green with a bluish tinge of color. On a cross-section, it is almost white to light yellow in color.

Active ingredient

Esomeprazole

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as prescribed by a doctor, Children as prescribed by a doctor, Pregnant women as prescribed by a doctor, Children over 12 years of age

Indications

Gastric and duodenal ulcers, Gastrointestinal infections caused by Helicobacter Pylori, Reflux Esophagitis