Nexium, pellets and 10 mg 28 pcs

Pharmacotherapeutic group: A gastric gland secretion reducing agent – proton pump inhibitor

ATX code: A02BC05

Pharmacological Properties

.Pharmacodynamics

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

Mechanism of action

. Esomeprazole is a weak base that is converted to its active form 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, with inhibition of both basal and stimulated hydrochloric acid secretion.

Influence on gastric hydrochloric acid secretion

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

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

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

The healing of reflux esophagitis occurred in approximately 78% of patients after 4 weeks of therapy and in 93% after 8 weeks of therapy with Nexium® at a dose of 40 mg.

The treatment with Nexium® in a dose of 20 mg twice daily in combination with appropriate antibiotics for one week leads to 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 drugs that reduce gastric gland secretion to heal the ulcer and relieve symptoms.

Nexium® has been shown to be effective in peptic ulcer bleeding confirmed by endoscopic examination.

Application in GERD in children (ages 1-11 years)

Healing of erosive esophagitis confirmed by endoscopic study data was observed in 93.3% of patients aged 1-11 years after 8 weeks of therapy with Nexium®. Patients with body weight less than 20 kg took Nexium® in a daily dose of 5 mg or 10 mg, and patients with body weight over 20 kg – in a daily dose of 10 mg or 20 mg.

Other effects related to inhibition of hydrochloric acid secretion

During treatment with drugs that decrease gastric gland secretion, plasma gastrin concentration increases as a result of decreased hydrochloric acid secretion. Because of the decrease in hydrochloric acid secretion, chromogranin A (CgA) concentrations are increased. Increased CgA concentrations may affect the results of neuroendocrine tumor screenings. To prevent this effect, therapy with proton pump inhibitors should be stopped 5-14 days before CgA concentration testing. If the CgA concentration has not returned to normal during this time, the study should be repeated.

In children and adult patients treated with esomeprazole for a long time, an increase in enterochromaffin-like cells has been observed, probably due to an increase in plasma gastrin concentration. 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 due to physiological changes resulting from a pronounced inhibition of hydrochloric acid secretion. The cysts are benign and undergo reverse development.

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

Nexium® showed better efficacy compared to ranitidine for gastric ulcer healing in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors.

The Nexium® showed high efficacy in the prevention of gastric and duodenal ulcers in patients treated with NSAIDs (age group over 60 years and/or with a history of peptic ulcer), including selective COX-2 inhibitors.

Pharmacokinetics

Absorption and distribution. Esomeprazole is unstable in an acidic environment, so enteric-coated pellets are used for oral administration. Under in vivo conditions, only a small part of esomeprazole is converted to the R isomer. The drug is rapidly absorbed: maximum plasma concentration is reached 1-2 hours after administration. Absolute bioavailability of esomeprazole after a single dose of 40 mg is 64% and increases to 89% after daily dosing. For the 20 mg dose of esomeprazole these figures are 50% and 68%, respectively. The volume of distribution at equilibrium concentration in healthy subjects is approximately 0.22 l/kg body weight. Esomeprazole is 97% bound to plasma proteins.

Eating slows down and reduces absorption of esomeprazole in the stomach, but this has no significant effect on the effectiveness of inhibiting hydrochloric acid secretion.

Metabolism and excretion. Esomeprazole undergoes metabolism involving the cytochrome P450 system. The main part is metabolized with the participation of the specific polymorphic isoenzyme CYP2C19, with the formation of hydroxylated and desmethylated metabolites of esomeprazole. The remainder is metabolized by the CYP3A4 isoenzyme; this produces esomeprazole sulfo-derivative, which is the main plasma-detectable metabolite.

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

The total clearance is approximately 17 l/h after a single dose of the drug and 9 l/h after multiple doses. The elimination half-life is 1.3 hours with systemic administration once daily. The area under the curve “concentration

times” (AUC) increases with repeated administration of esomeprazole. The dose-dependent increase in AUC with repeated administration of esomeprazole is nonlinear, which is a consequence of a decrease in metabolism during “first passage” through the liver and a decrease in systemic clearance, probably caused by inhibition of the CYP2C19 isoenzyme by esomeprazole and/or its sulfo-derivatives. When administered once daily, esomeprazole is completely eliminated from the blood plasma between doses and does not cumulate.

The main metabolites of esomeprazole do not affect gastric acid secretion. When administered orally, up to 80% of the dose is excreted as metabolites in the urine, the remainder is excreted in the feces. Less than 1% of unchanged esomeprazole is detected in the urine.

Peculiarities of pharmacokinetics in some groups of patients. In approximately 2.9±1.5% of the population the activity of CYP2C19 isoenzyme is reduced. In these patients the metabolism of esomeprazole is mainly due to the action of CYP3A4. When systemically administered with 40 mg of esomeprazole once daily, the average AUC is 100% higher than that of patients with increased CYP2C19 isoenzyme activity. Mean values of maximum plasma concentrations in patients with decreased isoenzyme activity are increased by approximately 60%. These characteristics do not affect the dose and route of administration of esomeprazole.

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 30% higher than in men. There are no differences in pharmacokinetics in men and women when taking the drug once daily. These characteristics do not affect the dose and route of administration of esomeprazole.

The metabolism of esomeprazole may be impaired in patients with mild to moderate hepatic impairment. In patients with severe hepatic insufficiency the metabolic rate is reduced, resulting in a 2-fold increase in the AUC value for esomeprazole. For patients with severe hepatic impairment, the maximum daily dose of 20 mg should not be exceeded. No cumulation of esomeprazole and its major metabolites has been observed when administered once daily.

There have been no studies of pharmacokinetics in patients with renal insufficiency. Since the kidneys do not excrete esomeprazole itself, but its metabolites, it can be assumed that the metabolism of esomeprazole in patients with renal impairment is not altered.

In children aged 12-18 years after repeated administration of 20 mg and 40 mg of esomeprazole, the AUC and time to peak plasma concentration (TCmax) were similar to the AUC and TCmax values in adults.

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 receiving 20 mg of esomeprazole.

In children aged 1-11 years after repeated administration of 20 mg of esomeprazole, the AUC value was 6-11 times higher than the AUC value in adolescents and adults when receiving 20 mg of esomeprazole.

Indications

Gastroesophageal reflux disease (GERD):

Pharmacological effect

Pharmacotherapeutic group: drugs for the treatment of acid-related diseases; antiulcer agents and agents for the treatment of gastroesophageal reflux disease (GERD); proton pump inhibitors.

ATX code: A02BC05

Mechanism of action

Esomeprazole is a weak base that transforms into an 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, thereby inhibiting both basal and stimulated secretion of hydrochloric acid.

Pharmacodynamic effects

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

Clinical effectiveness

Effect on the secretion of hydrochloric acid in the stomach

The effect of esomeprazole develops within 1 hour after oral administration of 20 mg or 40 mg. 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 decreased by 90% (when measuring the acid concentration 6-7 hours after taking the drug on the 5th day of therapy).

In patients with GERD and clinical symptoms, after 5 days of daily oral esomeprazole 20 mg or 40 mg, intragastric pH values ​​above 4 were maintained for an average of 13 and 17 hours out of 24 hours. While taking esomeprazole at a dose of 20 mg per day, intragastric pH above 4 was maintained for at least 8, 12 and 16 hours in 76%, 54% and 24% of patients, respectively. For 40 mg esomeprazole, the ratios were 97%, 92% and 56%, respectively.

A correlation was found between the concentration of the drug in plasma and the inhibition of hydrochloric acid secretion (the AUC parameter was used to assess the concentration).

The therapeutic effect achieved by inhibiting the secretion of hydrochloric acid

When taking Nexium 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 Nexium at a dose of 20 mg 2 times a day in combination with appropriate antibiotics for one week leads to 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 reduce the secretion of gastric glands to heal the ulcer and eliminate symptoms.

Nexium has been shown to be effective in treating bleeding from peptic ulcers, confirmed by endoscopic examination.

Use for GERD in children (aged 1–11 years)

Healing of erosive esophagitis, confirmed by endoscopic examination, was observed in 93.3% of patients aged 1–11 years after 8 weeks of therapy with Nexium. Patients weighing less than 20 kg took Nexium at a daily dose of 5 mg or 10 mg, and patients weighing more than 20 kg took a daily dose of 10 mg or 20 mg.

Other effects associated with inhibition of hydrochloric acid secretion

During treatment with drugs that reduce the secretion of gastric glands, the concentration of gastrin in the 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. Increased concentrations of CgA may affect the results of examinations for the detection of neuroendocrine tumors. To prevent this effect, therapy with proton pump inhibitors should be suspended 5–14 days before CgA concentration testing. If during this time the CgA concentration has not returned to normal, the study should be repeated.

In children and adult patients receiving esomeprazole for a long time, an increase in the number of enterochromaffin-like cells was observed, probably associated with an increase in plasma gastrin concentrations. This phenomenon has no clinical significance.

Patients who took drugs that reduce the secretion of gastric glands for a long period of time were more likely to experience the formation of glandular cysts in the stomach. 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 that 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 Salmonella spp., Campylobacter spp. and, in hospitalized patients, probably Clostridium difficile.

Nexium showed better efficacy than ranitidine in healing gastric ulcers in patients treated with NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors.

The drug Nexium has shown high effectiveness in preventing gastric and duodenal ulcers in patients receiving NSAIDs (age group over 60 years and/or with a history of peptic ulcers), including selective COX-2 inhibitors.

Pharmacokinetic properties

Absorption

Esomeprazole is unstable in an acidic environment, so enteric-coated pellets are used for oral administration. Under in vivo conditions, only a small portion of esomeprazole is converted to the R-isomer. The drug is rapidly absorbed: maximum plasma concentration is achieved 1–2 hours after administration. The absolute bioavailability of esomeprazole after a single dose of 40 mg is 64% and increases to 89% with daily dosing once daily. For a dose of 20 mg esomeprazole, these figures are 50% and 68%, respectively. 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 hydrochloric acid secretion.

Distribution

The volume of distribution at steady state concentration in healthy people is approximately 0.22 l/kg body weight. Esomeprazole is 97% bound to plasma proteins.

Biotransformation

Esomeprazole is metabolized via the cytochrome P450 system. The main part is metabolized with the participation of a specific polymorphic isoenzyme CYP2C19, resulting in the formation of hydroxylated and demethylated metabolites of esomeprazole. The remainder is metabolized by the CYP3A4 isoenzyme; this produces a sulfo derivative of esomeprazole, which is the main metabolite detected in plasma.

Elimination

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

The total clearance is approximately 17 l/h after a single dose of the drug and 9 l/h after repeated doses. The half-life is 1.3 hours when taken systematically once a day. The AUC value increases with repeated dosing of esomeprazole. The dose-dependent increase in AUC with repeated administration of esomeprazole is non-linear, which is a consequence of a decrease in first-pass metabolism through the liver, as well as a decrease in systemic clearance, probably caused by inhibition of the CYP2C19 isoenzyme by esomeprazole and/or its sulfo 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. When administered orally, up to 80% of the dose is excreted in the form of metabolites in the urine, the rest is excreted in feces. Less than 1% of unchanged esomeprazole is found in urine.

Pharmacokinetics in special groups of patients

Approximately 2.9±1.5% of the population has reduced activity of the CYP2C19 isoenzyme. In these patients, esomeprazole is metabolized primarily through the action of CYP3A4. When systematically taking 40 mg of esomeprazole once a day, the average AUC value is 100% higher than 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 administration of esomeprazole.

Floor

After a single dose of 40 mg of esomeprazole, the average AUC value in women is 30% higher than that in men. When taking the drug daily once a day, there are no differences in pharmacokinetics between men and women. These features do not affect the dose and method of administration of esomeprazole.

Elderly patients

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

Patients with impaired renal function

Pharmacokinetic studies have not been conducted in patients with renal failure. Since it is not esomeprazole itself that is excreted through the kidneys, but its metabolites, it can be assumed that the metabolism of esomeprazole in patients with renal failure does not change.

Patients with liver dysfunction

In patients with mild to moderate hepatic impairment, the metabolism of esomeprazole may be impaired. In patients with severe liver failure, the metabolic rate is reduced, which leads to a 2-fold increase in the AUC value for esomeprazole. For patients with severe liver failure, the maximum daily dose should not exceed 20 mg. When taken once a day, no accumulation of esomeprazole and its main metabolites was observed.

Children

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

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

Special instructions

Impact on the ability to drive vehicles and operate machinery
Due to the fact that dizziness, blurred vision and drowsiness may occur during therapy with Nexium, caution should be exercised when driving vehicles and other machinery.

Active ingredient

Esomeprazole

Composition

Active ingredient: esomeprazole.
Each packet contains 10 mg esomeprazole (as magnesium salt trihydrate).

Full list of excipients:
Methacrylic acid and ethyl acrylate copolymer (1:1)
Talc
Sucrose, spherical granules (sugar, spherical granules) (size 0.250-0.355 mm)
Hyprolose
Hypromellose
Triethyl citrate
Magnesium stearate
Glycerol monostearate 40-55
Polysorbate 80
Dextrose
Crospovidone
Xanthan gum
Anhydrous citric acid
Yellow iron oxide dye

Pregnancy

Pregnancy
Currently, there is not enough data on the use of Nexium during pregnancy. The results of epidemiological studies of omeprazole, which is a racemic mixture, showed the absence of fetotoxic effects or impaired fetal development.
When esomeprazole was administered to animals, no direct or indirect negative effects on the development of the embryo or fetus were detected. The introduction of a racemic mixture of the drug also did not have any negative effects on animals during pregnancy, childbirth, or during postnatal development.
The drug should be prescribed to pregnant women only if the expected benefit to the mother outweighs the possible risk to the fetus.
Lactation
It is not known whether esomeprazole is excreted in breast milk, so Nexium should not be used during breastfeeding.

Contraindications

Hypersensitivity to esomeprazole, substituted benzimidazoles or any of the excipients.

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

Children under 1 year of age or body weight less than 10 kg (due to the lack of data on the effectiveness and safety of the drug in this group of patients).

Children aged 1–4 years for indications other than the treatment of erosive esophagitis and symptomatic treatment of GERD.

Children aged 4–11 years for indications other than the treatment of erosive esophagitis, symptomatic treatment of GERD and treatment of duodenal ulcer associated with Helicobacter pylori, as part of combination therapy.

Children over 12 years of age for indications other than GERD and treatment of duodenal ulcer associated with Helicobacter pylori, as part of combination therapy.

Esomeprazole should not be taken together with atazanavir and nelfinavir.

Special instructions and precautions for use

With caution

Severe renal failure (experience is limited).

Special instructions

If any alarming symptoms are present (for example, significant spontaneous weight loss, repeated vomiting, dysphagia, vomiting blood or melena), as well as the presence of a gastric ulcer (or suspected gastric ulcer), the presence of a malignant neoplasm should be excluded, since treatment with Nexium may lead to improvement of symptoms and delay the diagnosis.

In rare cases, in patients who took omeprazole for a long time, histological examination of biopsies of the mucous membrane of the gastric body revealed atrophic gastritis.

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

Patients taking Nexium “as needed” should be instructed to contact their physician if their symptoms change. Taking into account fluctuations in the concentration of esomeprazole in plasma when prescribing therapy “as needed”, the interaction of the drug with other drugs should be taken into account. When prescribing Nexium for the 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, therefore, when prescribing eradication therapy to patients receiving other drugs metabolized by the CYP3A4 isoenzyme (for example, cisapride), it is necessary to take into account possible contraindications and interactions of clarithromycin with these drugs.

According to the results of the studies, a pharmacokinetic/pharmacodynamic interaction was noted between clopidogrel (loading dose of 300 mg and maintenance dose of 75 mg/day) and esomeprazole (40 mg/day orally), which leads to a decrease in the exposure of the active metabolite of clopidogrel by an average of 40% and a decrease in the maximum inhibition of ADP-induced platelet aggregation by an average of 14%. Therefore, the simultaneous use of esomeprazole and clopidogrel should be avoided.

Individual observational studies indicate that proton pump inhibitor therapy may modestly increase the risk of osteoporosis-related fractures, but other similar studies have not reported an increased risk.

Randomized, double-blind, controlled clinical trials of omeprazole and esomeprazole, including two open-label studies of long-term therapy (more than 12 years), did not confirm the association of osteoporotic fractures with the use of proton pump inhibitors.

Although a causal relationship between the use of omeprazole/esomeprazole and osteoporotic fractures has not been established, patients at risk of developing osteoporosis or osteoporotic fractures should be under appropriate clinical supervision.

Excipients

Nexium contains sucrose and is therefore contraindicated in patients with hereditary fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency.

Children

Long-term use of the drug is not indicated for children and adolescents under 12 years of age.

Side Effects

Summary of Adverse Reactions

The following are undesirable reactions, independent of the dosage regimen of the drug, noted during clinical trials and during post-marketing use of the drug.

The frequency of adverse reactions is given in the following gradation: very often (≥ 1/10), often (≥ 1/100, but < 1/10), infrequently (≥ 1/1000, but < 1/100), rarely (≥ 1/10000, but < 1/1000), very rarely (< 1/10000).

From the skin and subcutaneous tissues Uncommon: dermatitis, itching, rash, urticaria; Rarely: alopecia, photosensitivity;

Very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders Rare: arthralgia, myalgia;

Very rare: muscle weakness.

From the nervous system: often: headache;

Uncommon: dizziness, paresthesia, drowsiness;

Rarely: taste disturbance.

Mental disorders Uncommon: insomnia;

Rarely: depression, agitation, confusion;

Very rare: hallucinations, aggressive behavior.

From the gastrointestinal tract

Common: abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting;

Uncommon: dry mouth;

Rarely: stomatitis, gastrointestinal candidiasis;

Very rare: microscopic colitis.

From the liver and biliary tract

Uncommon: increased activity of liver enzymes;

Rarely: hepatitis (with or without jaundice);

Very rare: liver failure, encephalopathy in patients with liver disease.

Genital and breast disorders Very rare: gynecomastia.

From the blood and lymphatic system Rarely: leukopenia, thrombocytopenia;

Very rare: agranulocytosis, pancytopenia.

From the immune system

Rare: hypersensitivity reactions (eg, fever, angioedema, anaphylactic reaction/anaphylactic shock).

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

From the kidneys and urinary tract Very rarely: interstitial nephritis.

From the side of the organ of vision Rarely: blurred vision.

Metabolism and nutrition: Uncommon: peripheral edema; Rarely: hyponatremia;

Very rare: hypomagnesemia; hypocalcemia due to severe hypomagnesemia, hypokalemia due to hypomagnesemia.

General disorders

Rarely: malaise, sweating.

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 can lead to a decrease or increase in the absorption of drugs, the absorption of which depends on the acidity of the environment. Like other drugs that reduce gastric acidity, treatment with esomeprazole may result in decreased absorption of ketoconazole, itraconazole and erlotinib, and increased absorption of drugs such as digoxin. Co-administration of omeprazole 20 mg once daily with digoxin increases the bioavailability of digoxin by 10% (bioavailability of digoxin increased by up to 30% in 20% of 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 omeprazole therapy may affect the absorption of antiretroviral drugs. Interaction at the level of the CYP2C19 isoenzyme is also possible. When omeprazole is co-administered with certain antiretroviral drugs, such as atazanavir and nelfinavir, a decrease in their serum concentrations is observed during omeprazole therapy. Therefore, their simultaneous use is not recommended. Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg in healthy volunteers resulted in a significant decrease in the bioavailability of atazanavir (area under the concentration-time curve – AUC, maximum (Cmax) and minimum (Cmin) concentrations decreased by approximately 75%). Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on the bioavailability of atazanavir.

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

Esomeprazole inhibits CYP2C19, the main isoenzyme involved in its metabolism. Accordingly, the combined use of esomeprazole with other drugs in the metabolism of which the CYP2C19 isoenzyme is involved, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., may lead to increased plasma concentrations of these drugs, which, in turn, may require a dose reduction. This interaction is especially important to remember when using Nexium in the “as needed” mode. When 30 mg of esomeprazole and diazepam, which is a substrate of the CYP2C19 isoenzyme, are taken together, a decrease in the clearance of diazepam by 45% is observed.

The use of esomeprazole at a dose of 40 mg led to an increase in residual phenytoin concentrations in patients with epilepsy by 13%. In this regard, it is recommended to monitor plasma concentrations of phenytoin when starting treatment with esomeprazole and when discontinuing it.

The use of omeprazole at a dose of 40 mg once daily led to an increase in the area under the concentration-time curve and Cmax of voriconazole (CYP2C19 isoenzyme substrate) by 15% and 41%, respectively.

Co-administration of warfarin with 40 mg esomeprazole does not lead to a change in coagulation time in patients taking warfarin for a long time. However, several cases of clinically significant increases in INR (international normalized ratio) have been reported with the combined use of warfarin and esomeprazole. It is recommended to monitor the INR at the beginning and at the end of the combined use of esomeprazole and warfarin or other coumarin derivatives.

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

The clinical significance of this interaction is unclear. In a prospective study in patients receiving placebo or omeprazole 20 mg/day. concomitantly with therapy with clopidogrel and acetylsalicylic acid (ASA), and when analyzing the clinical outcomes of large-scale randomized trials, there was no increase in the risk of cardiovascular complications with the combined use of clopidogrel and proton pump inhibitors, including esomeprazole.

The results of a number of observational studies are contradictory and do not provide a clear answer about the presence or absence of an increased risk of thromboembolic cardiovascular complications during the combined use of clopidogrel and proton pump inhibitors.

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

Esomeprazole, like omeprazole, inhibits the CYP2C19 isoenzyme. Co-administration of cilostazol and 40 mg of omeprazole leads to an increase in the pharmacokinetic parameters of cilostazol in healthy volunteers: Cmax and AUC by 18% and 26%, respectively. Similar parameters of one of the active metabolites of cilostazol increase by 29% and 69%, respectively.

Co-administration of cisapride with 40 mg of esomeprazole leads to an increase in the pharmacokinetic parameters of cisapride in healthy volunteers: AUC by 32% and half-life by 31%, but the maximum plasma concentration of cisapride does not change significantly. The slight prolongation of the QT interval, which was observed with cisapride monotherapy, did not increase with the addition of Nexium.

With the simultaneous use of esomeprazole and tacrolimus, an increase in the concentration of tacrolimus in the blood serum was noted.

In some patients, an increase in the concentration of methotrexate was observed during combined use with proton pump inhibitors. When using high doses of methotrexate, the possibility of temporary withdrawal of esomeprazole should be considered.

The drug Nexium does not cause clinically significant changes in the pharmacokinetics of amoxicillin and quinidine.

Studies evaluating short-term co-administration of esomeprazole and naproxen or rofecoxib did not reveal a clinically significant pharmacokinetic interaction.

Effect of drugs on the pharmacokinetics of esomeprazole

The isoenzymes CYP2C19 and CYP3A4 are involved in the metabolism of esomeprazole. The combined use of esomeprazole with clarithromycin (500 mg 2 times a day), which inhibits the CYP3A4 isoenzyme, leads to an increase in the AUC value of esomeprazole by 2 times. Co-administration of esomeprazole and a combined inhibitor of CYP3A4 and CYP2C19 isoenzymes, such as voriconazole, may result in 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 the isoenzymes CYP2C19 and CYP3A4, such as rifampicin and St. John’s wort preparations, when used together with esomeprazole, may lead to a decrease in the concentration of esomeprazole in the blood plasma by accelerating the metabolism of esomeprazole.

More information about special groups

Dose adjustment of esomeprazole may be required in patients with severe liver dysfunction and with long-term use.

Children

Long-term use of the drug is not indicated for children and adolescents under 12 years of age.

Overdose

Symptoms
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 Nexium did not cause any negative effects.
Treatment
There is no known antidote for esomeprazole. Esomeprazole binds well to plasma proteins, so dialysis is ineffective. In case of overdose, symptomatic and general supportive treatment should be provided.

Storage conditions

At a temperature not exceeding 25°C, in places inaccessible to children.

Shelf life

3 years.
The prepared suspension can be taken orally immediately / administered through a nasogastric tube immediately or within 30 minutes after preparation. Unused suspension should be destroyed.

Manufacturer

AstraZeneca AB, Sweden