Esomeprazole-SZ, 20 mg 28 pcs

Pharmacotherapeutic group

Stomach gland secretion reducing agent – proton pump inhibitor

ATX code

A02BC05

Pharmacodynamics:

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

Mechanism of action

Esomeprazole is a weak base which becomes active in the highly acidic environment of the secretory tubules of the parietal cells of the gastric mucosa and inhibits the proton pump enzyme H+/K+-ATPase and inhibits both basal and stimulated hydrochloric acid secretion.

The effect on acid secretion in the stomach

The action of esomeprazole develops within 1 hour after oral administration of 20 mg or 40 mg. When administered daily for 5 days in a dose of 20 mg once daily, the mean maximum concentration of hydrochloric acid after pentagastrin stimulation decreased by 90% (when acid concentration was measured 6-7 hours after taking the drug on therapy day 5).

In patients with gastroesophageal reflux disease (GERD) and the presence of clinical symptoms after 5 days of daily oral administration of esomeprazole at a dose of 20 mg or 40 mg, intragastric pH values above 4 were maintained for an average of 13 and 17 hours out of 24 hours. On background administration of esomeprazole at a dose of 20 mg per day, intragastric pH values above 4 were maintained for at least 8 12 and 16 hours in 76% 54% and 24% of patients, respectively. For 40 mg esomeprazole this ratio is 97% 92% and 56%, respectively.

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

Therapeutic effect achieved as a result of inhibition of hydrochloric acid secretion

When taking Esomeprazole-SZ at a dose of 40 mg healing of reflux esophagitis occurred in approximately 78% of patients after 4 weeks of therapy and in 93% – after 8 weeks of therapy.

Treatment with Esomeprazole-SZ in a dose of 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 one-week course of eradication do not require subsequent monotherapy with gastric gland-reducing drugs for ulcer healing and relief of symptoms.

The efficacy of Esomeprazole-SZ for peptic ulcer bleeding has been demonstrated in a study of patients with endoscopically confirmed peptic ulcer bleeding.

Other effects associated with inhibition of hydrochloric acid secretion

During treatment with drugs that reduce gastric gland secretion, plasma gastrin concentrations are increased as a result of decreased acid secretion. Due to the decrease in hydrochloric acid secretion, chromogranin A (CgA) concentrations increase. Increased concentration of CgA may affect the results of examinations for detection of neuroendocrine tumors. To prevent this effect, esomeprazole should be temporarily stopped 5-14 days before the CgA examination. If CgA concentrations have not returned to normal during this time, the study should be repeated.

In some patients on long-term esomeprazole therapy, an increase in enterochromaffin-like cells is probably associated with an increase in plasma gastrin concentrations. This phenomenon has no clinical significance.

In patients taking drugs that reduce gastric gland secretion over a long period of time formation of glandular cysts in the stomach is more often observed. These phenomena are caused by physiological changes resulting from a pronounced inhibition of hydrochloric acid secretion. The cysts are benign and undergo reverse development.

The use of drugs inhibiting the secretion of hydrochloric acid in the stomach, including proton pump inhibitors, is accompanied by an increase in the content of microbial flora normally present in the gastrointestinal tract. Use of proton pump inhibitors may lead to a slight increase in the risk of gastrointestinal tract infections caused by bacteria of the genus Salmonella spp. and Campylobacter spp. and in hospitalized patients probably Clostridium difficile.

In two comparative studies with ranitidine, esomeprazole showed better gastric ulcer healing in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2).

In two studies, esomeprazole showed high efficacy in the prevention of gastric and duodenal ulcers in patients who received NSAIDs (age group over 60 years and/or with a history of peptic ulcer) including selective COX-2 inhibitors.

Pharmacokinetics:

Esomeprazole is unstable in acidic environments so it is taken orally in the form of enteric soluble capsules containing pellets of the drug which are also resistant to gastric juice.

In in vivo, a small portion of esomeprazole is converted to the R-isomer. Esomeprazole is rapidly absorbed reaching peak plasma concentrations about 1 to 2 hours after oral administration.

The absolute bioavailability is 64% after a single dose of 40 mg which increases to 89% after daily dosing of esomeprazole once daily. Bioavailability for esomeprazole in a dose of 20 mg is 50% and 68%, respectively. The volume of distribution in equilibrium in healthy volunteers is approximately 022 l/kg body weight.

Esomeprazole is 97% bound to plasma proteins.

Eating slows down and reduces absorption of esomeprazole and has no significant clinical relevance.

Metabolism and excretion

Esomeprazole is fully metabolized with participation of the cytochrome P450 isoenzyme system in the liver. Most of it is metabolized with participation of the polymorphic isoenzyme CYP2C19, which is responsible for the formation of hydroxy- and demethylated metabolites. The remaining part of esomeprazole is metabolized by the CYP3A4 isoenzyme responsible for the formation of the main plasma metabolite esomeprazole sulfone.

The total plasma clearance after a single dose is about 17 l/h and 9 l/h after multiple doses.

The elimination half-life (T1/2) is 13 h after prolonged administration once daily.

The area under the curve “concentration – time” (AUC) increases with repeated administration. The dose-dependent increase in AUC with repeated administration is nonlinear due to a decrease in metabolism during “first passage” through the liver, a decrease in clearance probably caused by inhibition of the CYP2C19 isoenzyme by esomeprazole and/or its sulfo-containing metabolite. With a single daily dose, esomeprazole is completely eliminated from the blood plasma between doses.

Esomeprazole does not cumulate.

The main metabolites of esomeprazole do not affect the secretion of hydrochloric acid in the stomach. Almost 80% of the oral dose of esomeprazole is excreted by the kidneys as metabolites and the rest is excreted through the intestine. Less than 1% of unchanged esomeprazole is found in the urine.

Pharmacokinetics in selected patient groups

In about 29±15% of the population the activity of CYP2C19 isoenzyme is decreased.

In these patients, esomeprazole is metabolized primarily by the CYP3A4 isoenzyme. After repeated administration of esomeprazole at a dose of 40 mg once daily, the average AUC is approximately 2 times higher than in patients with decreased CYP2C19 activity. The mean values of maximum plasma concentrations (Cmax) are increased by about 60%.

The metabolism of esomeprazole is not significantly altered in elderly patients (71-80 years).

After a single dose of 40 mg of esomeprazole, the average AUC in women is about 30% higher than in men. No further differences in pharmacokinetics were observed in both sexes when esomeprazole was taken systematically daily once daily. These peculiarities do not affect the dose and route of administration.

The metabolism of esomeprazole may be impaired in people with mild to moderate hepatic impairment. The metabolic rate is reduced in severe hepatic impairment, which is accompanied by a twofold increase in AUC. Therefore, the maximum daily dose of esomeprazole in these patients is 20 mg.

There have been no studies in patients with impaired renal function. Because esomeprazole metabolites rather than esomeprazole itself are excreted through the kidneys, the metabolism of esomeprazole does not change in these patients.

After repeated administration of 20 mg and 40 mg esomeprazole, the AUC and time to maximum concentration (TCmax) levels were similar in children aged 12-18 years and adults.

Indications

Gastroesophageal reflux disease:

Treatment of erosive reflux esophagitis;

Long-term maintenance treatment after healing of erosive reflux esophagitis to prevent recurrence;

Symptomatic treatment of gastroesophageal reflux disease.

Peptic ulcer disease of the stomach and duodenum

As part of the combined therapy:

– treatment of duodenal ulcer associated with Helicobacter pylori;

– prevention of recurrence of peptic ulcer associated with Helicobacter pylori.

Long-term acid suppressive therapy in patients who have had bleeding from a peptic ulcer (after intravenous administration of drugs that reduce gastric gland secretion, for the prevention of recurrence).

Patients taking long-term NSAIDs:

– healing of NSAID-associated gastric ulcers;

– prevention of NSAID-associated gastric and duodenal ulcers in patients at risk.

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

Active ingredient

Composition

1 capsule contains:

The active ingredient:

esomeprazole pellet substance – 89 mg,

esomeprazole magnesium trihydrate – 22.306 mg, in terms of esomeprazole – 20 mg,

[pellet core: esomeprazole magnesium trihydrate – 22.306 mg, sugar grits (sucrose, starch treacle) – 26.388 mg, sodium carbonate – 2.374 mg, povidone K-30 – 0.594 mg, sodium phosphate displaced – 2.374 mg, sodium lauryl sulfate – 0.445 mg; pellet shell: hypromellose (5cps) – 10.905 mg, titanium dioxide – 4.45 mg, talc – 3.856 mg, hypromellose phthalate – 13.913 mg, cetyl alcohol – 1.395 mg].

Auxiliary substances:

Solid gelatin capsules #3: Body: titanium dioxide – 2.0%, gelatin – up to 100% Cap: azorubin dye (carmazine dye) – 0.6619%, indigo carmine – 0.0286%, titanium dioxide – 0.6666%, gelatin – up to 100%.

How to take, the dosage

Ingestion. The tablet should be swallowed whole with liquids. The tablets should not be chewed or crushed.

Adults and children from 12 years of age

Gastroesophageal reflux disease

Treatment of erosive reflux esophagitis: 40 mg once daily for 4 weeks.

An additional 4-week course of treatment is recommended in cases where esophagitis does not heal or symptoms persist after the first course.

Long-term maintenance treatment after healing of erosive reflux esophagitis to prevent recurrence: 20 mg once daily.

Symptomatic treatment of gastroesophageal reflux disease: 20 mg once daily for patients without esophagitis. If after 4 weeks of treatment the symptoms do not disappear, further examination of the patient should be carried out. After elimination of symptoms it is possible to switch to “as needed” regimen, i.e. to take esomeprazole 20 mg once daily when symptoms recur. For patients taking NSAIDs who are at risk of gastric or duodenal ulcer, treatment on an “as needed” regimen is not recommended.

Adults

Gastric and duodenal ulcer

In combination therapy for eradication with Helicobacter pylori:

Treatment of duodenal ulcer associated with Helicobacter pylori: esomeprazole 20 mg, amoxicillin 1 g, and clarithromycin 500 mg. All drugs are taken twice a day for 1 week;

– prevention of recurrence of peptic ulcers associated with Helicobacter pylori: esomeprazole 20 mg, amoxicillin 1 g and clarithromycin 500 mg. All drugs are taken twice daily for 1 week.

Long-term acid suppressive therapy in patients who have had bleeding from a peptic ulcer (after intravenous use of gastric gland-lowering drugs to prevent recurrence)

Esomeprazole 40 mg once daily for 4 weeks after completion of intravenous therapy with gastric gland-lowering drugs.

Patients taking long-term NSAIDs:

– healing of NSAID-associated peptic ulcer: esomeprazole 20 mg or
40 mg once daily: treatment duration is 4-8 weeks;

– prevention of gastric and duodenal ulcers associated with taking NSAIDs: esomeprazole 20 mg or 40 mg once daily.

Conditions associated with pathological hypersecretion of gastric glands, including Zollinger-Ellison syndrome and idiopathic hypersecretion.

The recommended starting dose is esomeprazole 40 mg twice daily. Subsequently, the dose is adjusted individually; the duration of treatment is determined by the clinical picture of the disease. There is experience of using the drug in doses up to 120 mg twice daily.

Renal insufficiency: no dose adjustment is required. However, experience with esomeprazole in patients with severe renal impairment is limited; therefore, caution should be exercised when prescribing the drug in these patients (see section “Pharmacokinetics”).

Hepatic impairment: In mild to moderate hepatic impairment, no adjustment of the drug dose is required. For patients with severe hepatic insufficiency the maximum daily dose should not exceed 20 mg.

Elderly patients: No dose adjustment is required.

Interaction

The effect of esomeprazole on the pharmacokinetics of other drugs

The decrease in gastric hydrochloric acid secretion during treatment with esomeprazole and other proton pump inhibitors may lead to a decrease or increase in absorption of drugs whose absorption depends on the acidity of the environment. Like other drugs that reduce gastric acidity, treatment with esomeprazole may lead to decreased absorption of ketoconazole, itraconazole and erlotinib and increased absorption of drugs such as digoxin. Co-administration of omeprazole at a dose of 20 mg once daily and digoxin increased digoxin bioavailability by 10% (digoxin bioavailability was increased by up to 30% in two out of ten patients).

Omeprazole has been shown to interact with some antiretroviral drugs. The mechanisms and clinical significance of these interactions are not always known. An increase in pH during therapy with omeprazole may affect the absorption of antiretrovirals. There may also be an interaction at the level of CYP2C19 isoenzyme. When coadministration of omeprazole and some antiretroviral drugs such as atazanavir and nelfinavir during therapy with omeprazole, a decrease in their serum concentrations is noted. Therefore, their concomitant use is not recommended. Concomitant use of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg in healthy volunteers led to a significant decrease in bioavailability of atazanavir (AUC, Cmax and Cmin decreased by approximately 75%). Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir bioavailability.

Concomitant use of omeprazole and saquinavir showed increased serum concentrations of saquinavir; when used with some other antiretrovirals, their concentrations did not change. Given the similar pharmacokinetic and pharmacodynamic properties of omeprazole and esomeprazole, co-administration of esomeprazole with antiretrovirals such as atazanavir and nelfinavir is not recommended.

Esomeprazole inhibits CYP2C19, the main isoenzyme involved in its metabolism. Accordingly, co-administration of esomeprazole with other drugs whose metabolism involves the CYP2C19 isoenzyme, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., may lead to increased plasma concentrations of these drugs, which in turn may require dose reduction. This interaction is particularly important to keep in mind when using esomeprazole on an “as needed” regimen. Co-administration of esomeprazole 30 mg and diazepam, which is a substrate of CYP2C19 isoenzyme, decreases diazepam clearance by 45%.

The use of esomeprazole in dose of 40 mg led to increase of residual concentration of phenytoin in patients with epilepsy by 13%. Therefore, it is recommended to monitor plasma concentrations of phenytoin at the beginning of treatment with esomeprazole and at its withdrawal.

The use of omeprazole in dose of 40 mg once daily increased AUC and Cmax of voriconazole (substrate of CYP2C19 isoenzyme) by 15% and 41%, respectively.

The co-administration of warfarin with 40 mg of esomeprazole does not lead to changes in coagulation time in patients taking long-term warfarin. However, several cases of clinically significant increases in INR (international normalized ratio) have been reported when warfarin and esomeprazole are coadministered. It is recommended to monitor INR at the beginning and at the end of coadministration of esomeprazole and warfarin or other coumarin derivatives.

. Pharmacokinetic/pharmacodynamic interaction between clopidogrel (loading dose of 300 mg and maintenance dose of 75 mg/day) and esomeprazole (40 mg/day orally) has been reported, resulting in an average 40% decrease in exposure to the active metabolite clopidogrel and an average 14% decrease in maximum inhibition of ADP-induced platelet aggregation.

The clinical significance of this interaction is unclear. In a prospective study in patients receiving placebo or omeprazole at a dose of 20 mg/day concomitantly with clopidogrel and acetylsalicylic acid (ASA) therapy and in an analysis of clinical outcomes of large randomized trials, no increased risk of cardiovascular complications was shown when clopidogrel and proton pump inhibitors, including esomeprazole, were used together.

The results of several observational studies are inconsistent and do not provide a definitive answer about the presence or absence of an increased risk of thromboembolic cardiovascular complications with clopidogrel and proton pump inhibitors.

When clopidogrel was used together with a fixed combination of 20 mg of esomeprazole and 81 mg of ASA, exposure to the active metabolite clopidogrel was reduced by almost 40% compared with clopidogrel monotherapy, while maximum levels of inhibition of ADP-induced platelet aggregation were similar, which is likely due to the simultaneous administration of low-dose ASA.

The use of omeprazole at a dose of 40 mg resulted in an 18% and 26% increase in Cmax and AUC of cilostazol, respectively; for one of the active metabolites of cilostazol, the increase was 29% and 69%, respectively.

The co-administration of cisapride with 40 mg of esomeprazole increased pharmacokinetic parameters of cisapride in healthy volunteers: AUC by 32% and half-life by 31%, but the maximum concentration of cisapride in plasma was not significantly changed. Slight prolongation of the QT interval, which was observed with cisapride monotherapy, was not increased with the addition of esomeprazole (see section “Special Precautions”).

Concomitant use of esomeprazole and tacrolimus resulted in increased serum concentrations of tacrolimus.

In some patients, increased concentrations of methotrexate have been noted when coadministered with proton pump inhibitors. If high doses of methotrexate are used, temporary withdrawal of esomeprazole should be considered.

Esomeprazole does not cause clinically significant changes in pharmacokinetics of amoxicillin and quinidine.

Studies evaluating short-term co-administration of esomeprazole and naproxen or rofecoxib have shown no clinically significant pharmacokinetic interaction.

The effect of drugs on the pharmacokinetics of esomeprazole

The CYP2C19 and CYP3A4 isoenzymes are involved in the metabolism of esomeprazole. Concomitant use of esomeprazole with clarithromycin (500 mg 2 times per day) which inhibits the CYP3A4 isoenzyme results in a 2-fold increase in the AUC of esomeprazole. Concomitant use of esomeprazole and a combined CYP3A4 and CYP2C19 isoenzyme inhibitor such as voriconazole may lead to more than a 2-fold increase in the AUC of esomeprazole. No dose adjustment of esomeprazole is usually required in such cases. A dose adjustment of esomeprazole may be required in patients with severe hepatic impairment and long-term use.

Drugs inducing CYP2C19 and CYP3A4 isoenzymes, such as rifampicin and preparations of St. John’s wort, when used in combination with esomeprazole may lead to decreased plasma concentration of esomeprazole due to accelerated metabolism of esomeprazole.

Special Instructions

In the presence of any worrisome symptoms (e.g., significant spontaneous weight loss, recurrent vomiting, dysphagia, bloody vomiting, or melena) and the presence (or suspected presence) of a peptic ulcer, malignancy should be excluded, as treatment with esomeprazole may ameliorate symptoms and delay diagnosis.

In rare cases, histological examination of biopsy specimens of gastric body mucosa has revealed atrophic gastritis in patients who have taken omeprazole for a long time.

Patients who take the drug for a long period of time (especially more than a year) should be monitored regularly by a physician.

Patients taking esomeprazole “as needed” should be instructed to contact their physician if their symptoms change. Taking into account the fluctuations in plasma concentrations of esomeprazole when prescribing therapy on an “as needed” basis, the interaction of the drug with other medicinal products should be considered (see section “Interaction with other medicinal products”). When prescribing esomeprazole for eradication of Helicobacter pylori, the possibility of drug interactions for all components of triple therapy should be considered. Clarithromycin is a potent CYP3A4 inhibitor, therefore when prescribing eradication therapy for patients receiving other drugs metabolized with participation of CYP3A4 (for example, cisapride), it is necessary to consider possible contraindications and interactions of clarithromycin with these drugs.

Impact on laboratory values

Esomeprazole may cause elevation of chromogranin A levels, which may distort the results of examinations for neuroendocrine tumors. To avoid these problems, esomeprazole treatment should be temporarily withheld for at least five days before chromogranin A determination.

Esomeprazole, like all acid-lowering medications, may lead to decreased absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with risk factors for reduced absorption of vitamin B12 during long-term therapy.

When using proton pump inhibitors, especially when used in high doses and for a long period (> 1 year), there may be a risk of fractures of the femoral neck, carpal bones and vertebrae (especially in older patients).

Impact on driving, operating machinery

Because dizziness, blurred vision and drowsiness may occur during esomeprazole therapy, caution should be exercised when operating motor transport and other mechanisms.

Contraindications

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

Hereditary fructose intolerance, glucose-galactose malabsorption or sugar-isomaltase deficiency.

Children under 12 years of age (due to lack of data on the efficacy and safety of the drug in this group of patients) and children over 12 years of age for other indications, except for gastroesophageal reflux disease.

Esomeprazole should not be taken together with atazanavir and nelfinavir
(see section “Interaction with other medicinal products”).

The period of breastfeeding.

With caution

Severe renal impairment (experience of use is limited), pregnancy.

Side effects

The frequency of side effects is given as the following gradation (World Health Organization classification): very frequently (≥ 1/10); frequently (≥ 1/100, < 1/10); infrequently (≥ 1/1000, < 1/100); rarely (≥ 1/10000, < 1/1000); very rarely (< 1/10000).

Skin and subcutaneous tissue: infrequent – dermatitis, pruritus, rash, urticaria; rare – alopecia, photosensitization; very rare – erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Muscular and connective tissue disorders: rare – arthralgia, myalgia; very rare – muscle weakness.

Nervous system disorders: frequently – headache; infrequently – dizziness, paraesthesia, somnolence; rarely – taste disorders.

Psychiatric disorders: infrequent – insomnia; rare – depression, agitation, confusion; very rare – hallucinations, aggressive behavior.

Gastrointestinal tract: often – abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting; infrequent – dry mouth; rare – stomatitis, gastrointestinal candidiasis; very rare – microscopic colitis (confirmed histologically).

Hepatic and biliary tract disorders: infrequent – increased activity of “liver” enzymes; rare – hepatitis (with or without jaundice); very rare – liver failure, encephalopathy in patients with liver disease.

Gender and breast disorders: very rare – gynecomastia.

The blood and lymphatic system: rare – leukopenia, thrombocytopenia; very rare – agranulocytosis, pancytopenia.

The immune system: rarely – hypersensitivity reactions (e.g., fever, angioedema, anaphylactic reaction/anaphylactic shock).

Respiratory system, thoracic and mediastinal organs: rarely – bronchospasm.

Renal and urinary tract: very rare – interstitial nephritis.

Visual organ disorders: rare – blurred vision.

Metabolism and nutrition: infrequent peripheral edema; rare – hyponatremia; very rare – hypomagnesemia; hypocalcemia due to severe hypomagnesemia, hypokalemia due to hypomagnesemia.

General disorders: rarely – malaise, sweating.

Overdose

To date, extremely rare cases of intentional overdose have been described. Oral administration of esomeprazole at a dose of 280 mg was accompanied by general weakness and gastrointestinal symptoms. A single dose of 80 mg of esomeprazole caused no adverse effects. The antidote for esomeprazole is not known. Esomeprazole binds well to plasma proteins, so dialysis is ineffective.

In case of overdose, symptomatic and general supportive treatment is necessary.

Pregnancy use

There are currently insufficient data on the use of esomeprazole during pregnancy. The results of epidemiological studies of omeprazole, which is a racemic mixture, have shown no fetotoxic effects or impairment of fetal development.

No direct or indirect adverse effects on fetal or fetal development have been observed when esomeprazole is administered to animals. Administration of the racemic mixture of the drug also did not have any adverse effects on animals during pregnancy, delivery, and postnatal development.

The drug should be administered to pregnant women only when the expected benefit to the mother outweighs the possible risk to the fetus.

It is not known whether esomeprazole is excreted with the breast milk, so it is not recommended to prescribe esomeprazole while breastfeeding.

Similarities