Esomeprazole

Pharmacological properties

esomeprazole is the s-isomer of omeprazole, which reduces the secretion of gastric juice due to a specifically directed mechanism of action. it is a specific proton pump inhibitor (PPI) in the parietal cell. The r- and s-isomers of omeprazole exhibit the same pharmacodynamic activity.

Esomeprazole is a weak base, it concentrates and becomes active in the highly acidic environment of the secretory tubules of the parietal cell, where it inhibits the enzyme H⁺-TO⁺-ATPase is an acid pump, and also inhibits basal and stimulated secretion of acid.

After oral administration of 20 mg and 40 mg of esomeprazole, the effect occurs within an hour. After repeated use of 20 mg of esomeprazole once a day for 5 days, the average peak of acid release after stimulation with pentagastrin decreases by 90% when this indicator is determined 6-7 hours after taking the dose on the 5th day.

After 5 days of taking esomeprazole 20 mg and 40 mg orally, the pH of the stomach was above 4 on average for 13 and 17 hours, respectively, and more than 24 hours in patients with symptomatic reflux esophagitis. The proportion of patients in whom the pH of the stomach was above 4 for 8; 12 and 16 hours after taking 20 mg of esomeprazole, respectively 76; 54 and 24%. The appropriate proportions for esomeprazole 40 mg were 97; 92 and 56%.

When using AUC as an indirect indicator of plasma concentration, the dependence of the suppression of acid secretion on the exposure of the drug was demonstrated.

Therapeutic effects of suppressing the secretion of hydrochloric acid. Treatment with reflux esophagitis with esomeprazole 40 mg was successful in approximately 70% of patients after 4 weeks of treatment and in 93% after 8 weeks of treatment.

The use of esomeprazole 20 mg 2 times a day for 1 week together with the corresponding antibiotics led to the successful eradication of Helicobacter pylori in about 90% of patients. After such treatment for 1 week there was no need for further monotherapy with antisecretory drugs to successfully heal the ulcer and eliminate the symptoms of an uncomplicated duodenal ulcer.

Other effects associated with inhibition of hydrochloric acid secretion. During the use of antisecretory drugs, the concentration of gastrin in the blood plasma increases in response to a decrease in acid secretion. Chromogranin A also increases due to a decrease in the acidity of gastric juice.

It is possible that an increase in the number of enterochromaffin-like cells is associated with an increase in the level of gastrin in the blood plasma observed in some patients with prolonged use of esomeprazole.

Received reports of several cases of increased incidence of granular cysts in the stomach with prolonged use of antisecretory drugs. These phenomena are a physiological consequence of prolonged suppression of acid secretion; they are benign and reversible.

Reducing the acidity of gastric juice due to the use of any PPI increases in the stomach the number of bacteria present in the digestive tract normally. Treatment of PPIs may increase the risk of gastrointestinal infection caused, for example, by Salmonella or Campylobacter and, in hospital patients, possibly also Clostridium difficile.

Esomeprazole was more effective than ranitidine in treating gastric ulcers in patients taking NSAIDs, including selective COX-2 inhibitors.

Esomeprazole was effective in the prevention of gastric and duodenal ulcers in patients treated with NSAIDs (in patients over the age of 60 and / or with a history of ulcer).

Pharmacokinetics Esomeprazole absorption occurs rapidly, peak plasma concentrations are reached approximately 1–2 hours after a dose. The absolute bioavailability is 64% after applying a single dose of 40 mg and rises to 89% after repeated use once a day.For 20 mg of esomeprazole, the corresponding values ​​are 50 and 68%.

Eating slows down and reduces the absorption of esomeprazole, however, this does not affect the effect of esomeprazole with respect to acidity in the stomach cavity.

Distribution. The distribution volume in healthy volunteers in equilibrium is 0.22 l / kg body weight. Esomeprazole is 97% bound to plasma proteins.

Metabolism. Esomeprazole is completely metabolized using the Cytochrome 450 (CYP) system. The main part of the metabolism of esomeprazole depends on the polymorphic CYP 2C19, which is responsible for the formation of hydroxy and desmethyl metabolites of esomeprazole. Another part depends on the second specific isoform, CYP 3A4, which determines the formation of esomeprazolsulfone, the main metabolite in blood plasma.

The parameters below mainly reflect the pharmacokinetics of individuals with the functional enzyme CYP 2C19 (extensive metabolizers).

The total clearance from blood plasma is about 17 l / h after a single dose and about 9 l / h after repeated use. T_½ from blood plasma is about 1.3 hours after taking the dose once a day. Esomeprazole is completely excreted from blood plasma between doses without a tendency to cumulation when taking the drug 1 time per day.

The main metabolites of esomeprazole do not affect the secretion of gastric juice. About 80% of an oral dose of esomeprazole is excreted in the form of metabolites, others by the intestines. Less than 1% of the starting drug is detected in the urine.

Slow metabolizers. In approximately 2.9 ± 1.5% of the patient population, CYP 2C19 enzyme deficiency is noted (they are called slow metabolizers). In these individuals, the metabolism of esomeprazole is primarily mediated by CYP 3A4. After taking 40 mg of esomeprazole once a day, the average AUC in weak metabolizers is about 100% higher than in individuals with normal functioning of the CYP 2C19 enzyme (fast metabolizers). C_max in blood plasma increases by about 60%. These results have no effect on the dosage of esomeprazole.

Patients with impaired liver function. The metabolism of esomeprazole in patients with mild to moderate liver dysfunction may be impaired. The metabolic rate decreases in patients with severely impaired liver function, which leads to a 2-fold increase in AUC. Thus, the maximum dose for patients with severely impaired liver function is 20 mg. Esomeprazole and its metabolites do not tend to cumulate while taking the drug 1 time per day.

Patients with impaired renal function. Studies involving this category of patients have not been conducted. Since the kidneys are responsible for eliminating the metabolites of esomeprazole, and not the main parent compound, metabolic changes in patients with impaired renal function are not expected.

Elderly patients. The metabolism of esomeprazole does not undergo significant changes in elderly patients (from 71 to 80 years).

Children. After repeated use of 20 mg and 40 mg of esomeprazole, the total effect and time to reach C_max the drug in the blood plasma in children aged 12-18 years were the same as in adults.

Gender features. After a single dose of esomeprazole 40 mg, the average AUC in women is 30% higher than men. No gender-related differences were observed with repeated use of the drug once a day. These results do not affect the dosage of esomeprazole.

Indications

Gastroesophageal reflux disease:

• treatment of erosive reflux esophagitis;
• long-term treatment to prevent relapse;
• symptomatic treatment of gastroesophageal reflux disease.

In combination with Helicobacter pylori antibacterial agents for eradication:

• treatment of a duodenal ulcer associated with Helicobacter pylori;
• prevention of relapse of peptic ulcers in patients with ulcers caused by Helicobacter pylori.

Treatment and prevention of ulcers caused by prolonged use of NSAIDs:

• treatment of ulcers caused by NSAID therapy;
• prevention of gastric and duodenal ulcers in patients at risk in connection with NSAIDs.

Prevention of recurrence of bleeding from a stomach ulcer or duodenum after iv treatment with esomeprazole.

Treatment of Zollinger-Ellison syndrome.

Application

The drug is administered orally to adults and children over the age of 12 years. take the tablets whole 1 hour before a meal, drinking plenty of water. tablets should not be chewed or crushed. usually the duration of treatment is determined by the doctor.

Adults and children over 12 years old. Gastroesophageal reflux disease: treatment of erosive reflux esophagitis: 40 mg once a day for 4 weeks. An additional 4 weeks is recommended for patients with uncured esophagitis or its surviving symptoms.

Long-term treatment to prevent relapse: 20 mg 1 time per day.

Symptomatic treatment of gastroesophageal reflux disease: 20 mg once daily for patients without esophagitis. If symptom control is not achieved within 4 weeks of treatment, the patient should be examined. With the elimination of symptoms, their further control can be achieved by taking 20 mg once a day. For adults, you can apply the scheme "if necessary", which involves taking 20 mg once a day. For patients who use NSAIDs and are at risk of developing stomach ulcers or duodenal ulcers, further monitoring of symptoms using the “if necessary” regimen is not recommended.

Adults Treatment of a duodenal ulcer associated with Helicobacter pylori: 20 mg of esomeprazole with 1 g of amoxicillin and 500 mg of clarithromycin 2 times a day for 7 days.

Prevention of relapse of peptic ulcers in patients with ulcers caused by Helicobacter pylori: 20 mg of esomeprazole with 1 g of amoxicillin and 500 mg of clarithromycin 2 times a day for 7 days.

Treatment of gastric ulcers associated with the treatment of NSAIDs: the recommended dose is 20 mg once a day. The duration of treatment is 4-8 weeks.

Prevention of gastric and duodenal ulcers associated with the treatment of NSAIDs in patients at risk: the recommended dose is 20 mg once a day.

Prevention of relapse of bleeding of a stomach ulcer or duodenum after iv treatment with esomeprazole: 40 mg once a day for 4 weeks. The period of ingestion of esomeprazole should be preceded by therapy aimed at suppressing acidity, which consists in the use of esomeprazole in the form of a solution for infusion.

Treatment of Zollinger-Ellison syndrome: 40 mg 2 times a day. The dosage should be selected individually, the duration of treatment is determined by clinical indications. According to the clinical data, in most patients the disease can be controlled by taking 80–160 mg of esomeprazole per day. If the dose exceeds 80 mg / day, it should be divided into two doses.

Patients with impaired renal function. There is no need to adjust the dosage regimen. Due to the lack of experience with the use of esomerpazole in patients with severe renal failure, the drug should be prescribed with caution.

Impaired liver function. There is no need to adjust the dosage regimen for patients with mild to moderate impaired liver function. For patients with severely impaired liver function, the maximum dose of esomeprazole should not exceed 20 mg.

Elderly patients. There is no need to adjust the dosage regimen.

Contraindications

Known hypersensitivity to esomeprazole, substituted benzimidazoles or other components of the drug. simultaneous use with atazanavir, nelfinavir.

Side effects

The following side effects have been reported during clinical trials and after the introduction of esomeprazole into widespread medical practice. no dose-dependent effect was detected. adverse events were classified according to the frequency of occurrence: often (1/100, 1/10); infrequently (1/1000, 1/100); rarely (1/10 000, 1/1000) and very rarely (1/10 000).

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

From the immune system: rarely - hypersensitivity reactions, including fever, angioedema, anaphylactic reactions / shock.

From the side of metabolism and nutrition: infrequently - peripheral edema; rarely - hyponatremia; very rarely - hypomagnesemia; severe hypomagnesemia can lead to hypocalcemia.

Mental disorders: infrequently - insomnia; rarely - agitation, depression, confusion; very rarely - aggression, hallucinations.

From the nervous system: often - headache; infrequently - dizziness, weakness, paresthesia, drowsiness; rarely - a violation of taste.

From the side of the organ of vision: rarely - blurred vision.

On the part of the organ of hearing and labyrinth disorders: infrequently - vertigo.

From the respiratory system, chest and mediastinal organs: rarely - bronchospasm.

From the digestive tract: often - abdominal pain, constipation, diarrhea, bloating, nausea, vomiting; infrequently - dry mouth; rarely - stomatitis, gastrointestinal candidiasis; very rarely - microscopic colitis.

From the hepatobiliary system: infrequently - increased levels of liver enzymes; rarely - hepatitis with or without jaundice; very rarely - liver failure, encephalopathy in patients with liver disease.

From the skin and subcutaneous tissues: infrequently - dermatitis, itching, urticaria, rash; rarely - alopecia, photosensitivity; very rarely - erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

From the side of musculoskeletal and connective tissue: infrequently - a fracture of the hip, wrist or spine (see SPECIAL INSTRUCTIONS); rarely - arthralgia, myalgia; very rarely - muscle weakness.

On the part of the kidneys and urinary system: very rarely - interstitial nephritis (in some patients, simultaneously with renal failure).

From the reproductive system and mammary glands: very rarely - gynecomastia.

General disorders and disorders at the injection site: rarely - weakness, increased sweating.

special instructions

In the presence of symptoms (for example, pronounced weight loss, nausea, dysphagia, hematemiasis or melena) and in cases when a gastric ulcer is predicted or diagnosed, a malignant pathology should be excluded, since the use of esomeprazole can change the symptoms and delay the establishment of a correct diagnosis.

Patients who use the drug for a long time (especially more than a year) should be monitored regularly.

Patients using the drug as necessary should inform the doctor about changes in the nature of the symptoms.

When prescribing esomeprazole to eradicate Helicobacter pylori, possible drug interactions of all components of the triple therapy should be considered. Clarithromycin is a potent inhibitor of CYP 3A4, and its contraindications and interactions must be taken into account (if triple therapy is used in patients taking other drugs that are metabolized by CYP 3A4 along with esomeprazole, such as cisapride).

The use of PPIs may slightly increase the risk of gastrointestinal infections such as Salmonella and Campylobacter.

The use of esomeprazole, like all drugs that inhibit the secretion of acid, can lead to a decrease in the absorption of vitamin B₁₂ (cyanocobalamin) in connection with hypo- or achlorhydria.This should be considered in patients with reduced body stores or risk factors for decreased absorption of vitamin B₁₂ during prolonged therapy.

When using PPIs (including esomeprazole), cases of severe hypomagnesemia have been reported in patients who used PPIs for at least 3 months or, in most cases, for a year. Serious manifestations of hypomagnesemia, such as increased fatigue, tetany, delirium, cramps, dizziness, and ventricular arrhythmia, may develop. But the latter can begin unexpectedly and imperceptibly. Hypomagnesemia was eliminated after magnesium replacement therapy and cancellation of PPI. Patients with a predictable long course of treatment or taking PPIs with digoxin or drugs that can cause hypomagnesemia (e.g. diuretics) should monitor plasma levels of magnesium before starting treatment with PPIs and periodically during therapy.

The use of PPIs, especially in high doses and for a long time (1 year), can moderately increase the risk of hip, wrist or spinal fracture, mainly in the elderly or in the presence of other relevant risk factors. Observational studies suggest that PPIs may increase the overall risk of fractures by 10–40%. Some cases of fractures may be associated with other risk factors. Patients at risk of osteoporosis should undergo examination and receive treatment in accordance with current clinical recommendations, as well as ensure the supply of vitamin D and calcium in the required amount.

The simultaneous use of esomeprazole and atazanavir is not recommended. If the combination of atazanavir with PPI cannot be avoided, it is recommended to carefully monitor the patients condition in a hospital, as well as increase the dose of atazanavir to 400 mg from 100 mg of ritonavir; the dose of esomeprazole 20 mg should not be exceeded.

Esomeprazole is a CYP 2C19 inhibitor. At the beginning or end of treatment with esomeprazole, a potential interaction with drugs that are metabolized by CYP 2C19 should be considered. The interaction between clopidogrel and esomeprazole is noted. The clinical significance of this interaction has not been determined. As a precaution, the simultaneous use of this combination is recommended.

When prescribing esomeprazole, it is necessary to take into account its interaction with other drugs, which can affect the concentration of esomeprazole in the blood plasma. An increase in chromogranin A may interfere with the study to detect neuroendocrine tumors. To avoid obtaining false results, you should stop treatment with esomeprazole at least 5 days before measuring the level of chromogranin A.

Use during pregnancy and lactation. Period of pregnancy. Clinical data on the use of esomeprazole for the treatment of pregnant women are limited.

The results of studies of a large number of pregnant women taking a racemic mixture of omeprazole indicate the absence of malformation (impaired fetal development) and fetotoxic effects. Animal studies of esomeprazole have not revealed a direct or indirect negative effect on the development of the embryo / fetus. The study of the racemic mixture in animals did not show a direct or indirect negative effect on pregnancy, childbirth and postnatal development. The drug should be prescribed during pregnancy with caution.

The period of breastfeeding. No studies have been conducted with the participation of women who are breastfeeding. It is not known whether esomeprazole passes into breast milk. Therefore, esomeprazole should not be used during lactation.

Fertility. Studies on animal racemic mixtures of omeprazole have not shown effects on fertility.

Children. The drug is used in children over the age of 12 years.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. The drug does not affect the reaction rate when driving vehicles or working with other mechanisms. In case of dizziness and / or blurred vision, one should refrain from driving vehicles or other mechanisms.

Interactions

The effect of esomeprazole on the pharmacokinetics of other drugs. warfarin. in clinical studies of the use of 40 mg of esomeprazole in patients taking warfarin, it was shown that the coagulation time was within normal limits. however, after the drug was widely introduced into medical practice, there were several reports of a clinically significant increase in coagulation time; therefore, coagulation indicators should be monitored with the simultaneous use of esomeprazole and warfarin (or other coumarin derivatives).

Voriconazole Omeprazole, like esomeprazole, acts as a CYP 2C19 inhibitor. The concomitant use of omeprazole (40 mg once a day) led to an increase in C_max and AUC for voriconazole (CYP 2C19 substrate) by 15 and 41%, respectively.

Diazepam. The simultaneous use of 30 mg of esomeprazole leads to a decrease in clearance of the CYP 2C19-diazepam substrate by 45%.

Protease inhibitors. The interaction of omeprazole with some protease inhibitors (antiretroviral drugs) was noted. The clinical relevance and mechanisms of such interactions are not always known. Increasing the pH of gastric juice during the use of omeprazole may alter the absorption of protease inhibitors. Other interaction mechanisms may be associated with inhibition of SUR 2C19. In the case of the use of certain antiretroviral agents, such as atazanavir and nelfinavir, a decrease in the level of the latter in blood plasma was noted with simultaneous use with omeprazole. Therefore, the simultaneous administration of omeprazole and drugs such as atazanavir and nelfinavir is not recommended. The use of omeprazole (40 mg once a day) together with atazanavir 300 mg and ritonavir 100 mg in healthy volunteers led to a significant decrease in the effects of atazanavir (approximately 75% decrease in AUC, C_max, C_min) Increasing the dose of atazanavir to 400 mg did not compensate for the effect of omeprazole on the effectiveness of atazanavir. An increase in plasma levels of other antiretroviral agents such as saquinavir has been reported. There are also other antiretroviral drugs (darunavir, aprenavir, lopinavir), the plasma levels of which remained unchanged while being used with the drug.

Despite the similarity of the pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, it is not recommended to use esomeprazole simultaneously with atazanavir. The simultaneous use of esomeprazole with nelfinavir is contraindicated.

Clopidogrel. In healthy individuals, a pharmacokinetic / pharmacodynamic interaction was observed between clopidogrel (loading dose of 300 mg / daily maintenance dose of 75 mg) and esomeprazole (40 mg / day by mouth), which led to a decrease in the exposure of the active metabolite of clopidogrel by an average of 40% and a decrease in the maximum inhibitory activity (ADP-induced) relative to platelet aggregation by an average of 14%.

In a study in healthy individuals, in which the use of clopidogrel was studied together with a combination of 20 mg of esomeprazole and 81 mg of acetylsalicylic acid compared to clopidogrel in mono mode, a decrease in the exposure of the active metabolite of clopidogrel by almost 40% was noted. However, the maximum inhibitory activity (ATP-induced) in platelet aggregation in these individuals was the same in the clopidogrel and separate clopidogrel administration groups (esomeprazole + acetylsalicylic acid), which is probably due to the simultaneous administration of a low dose of acetylsalicylic acid.

A number of observational and clinical studies on pharmacokinetic / pharmacodynamic interactions have shown conflicting results regarding whether the risk of underlying cardiovascular events is increased if the patient receives clopidogrel along with an STI. As a warning, it is recommended to avoid the simultaneous use of clopidogrel.

Medicines that are metabolized by CYP 2C19. Esomeprazole inhibits CYP 2C19, the main enzyme that metabolizes esomeprazole. Therefore, when using esomeprazole in combination with drugs metabolized by CYP 2C19 (such as diazepam, citalopram, imipramine, clomipramine, phenytoin), the concentration of these drugs in blood plasma may be increased, therefore, their dose may need to be reduced. This circumstance should be taken into account, especially when prescribing esomeprazole as necessary.

Medicines whose absorption is pH dependent. Decreased acidity of gastric juice when using esomeprazole can increase or decrease the absorption of drugs, if their absorption depends on the acidity of gastric juice.

As with other drugs that reduce intragastric acidity, the absorption of drugs such as ketoconazole, itraconazole, as well as erlotinib, may decrease, while the absorption of drugs such as digoxin may increase with esomeprazole treatment. The simultaneous use of omeprazole (20 mg / day) and digoxin in healthy individuals increased the bioavailability of digoxin by 10% (in two out of ten people - by 30%). Digoxin toxicity has been reported rarely. But despite this, caution must be exercised when using esomeprazole in high doses in elderly patients. Enhanced therapeutic drug monitoring of digoxin should be carried out.

Methotrexate. An increase in the blood methotrexate level in some patients has been reported while taking it with PPI. If it is necessary to administer methotrexate in high doses, consideration should be given to temporarily discontinuing esomeprazole.

Tacrolimus. With the simultaneous use of esomeprazole, an increase in the level of tacrolimus in blood plasma has been reported. If this combination is used, renal function (creatinine clearance) should be monitored, plasma tacrolimus level should be monitored, and dose adjustment should be made if necessary.

Cisapride. In healthy volunteers, the simultaneous use of 40 mg of esomeprazole with cisapride leads to an increase in AUC by 32% and an increase in T_½ by 31%, but there was no noticeable increase in the peak level of cisapride in blood plasma. A moderately prolonged Q – T interval was observed separately after taking cisapride and did not increase with further use of cisapride in combination with esomeprazole.

Cilostazolum. Omeprazole, like esomeprazole, acts as a CYP 2C19 inhibitor. The use of omeprazole at a dose of 40 mg in healthy volunteers during the study led to an increase in C_max and AUC for cilostazol by 18 and 26%, respectively, and for one of its active metabolites, by 29 and 69%, respectively.

Phenytoin. The simultaneous use of 40 mg of esomeprazole leads to an increase in the level of phenytoin in blood plasma by 13% in patients with epilepsy. It is recommended that the concentration of phenytoin in the blood plasma be monitored when prescribing or discontinuing esomeprazole therapy.

The effect of other drugs on the pharmacokinetics of esomeprazole. Medicines that inhibit CYP 2C19, CYP 3A4, or both enzymes. Esomeprazole is metabolized by CYP 2C19 and CYP 3A4. The simultaneous use of esomeprazole and a CYP 3A4 inhibitor clarithromycin (500 mg 2 times a day) led to a doubling of the exposure (AUC) of esomeprazole.

The simultaneous use of esomeprazole and the combined inhibitor of CYP 2C19 and CYP 3A4 can lead to more than double the exposure of esomeprazole.Voriconazole (an inhibitor of CYP 2C19 and CYP 3A4) caused an increase in AUC of omeprazole by 280%. In such situations, dose adjustment of esomeprazole is not always needed. But dose adjustment should be performed in patients with severe hepatic insufficiency or in the case of the appointment of long-term treatment.

Medicines inducing CYP 2C19, CYP 3A4, or both enzymes. Drugs that induce CYP 2C19, CYP 3A4, or both enzymes (such as rifampicin or St. Johns wort grass) can lead to a decrease in plasma levels of esomeprazole by accelerating its metabolism.

Esomeprazole has not shown a clinically significant effect on the pharmacokinetics of amoxicillin or quinidine.

With the simultaneous short-term use of esomeprazole and naproxen or rofecoxib, clinically significant pharmacokinetic interactions were not observed.

Overdose

Data on overdose is limited. gastrointestinal symptoms and weakness are described after taking esomeprazole at a dose of 280 mg. a single dose of 80 mg esomeprazole will not cause severe side effects. special antidote is unknown. Esomeprazole binds to a large extent to plasma proteins, therefore it is not excreted by dialysis.

Treatment: symptomatic and supportive therapy.

Storage conditions

In the original packaging at a temperature not exceeding 25 ° C.