Emanera (Ezomeprazole)

1 enteric capsule contains:

active substance :

esomeprazole magnesium 20.645 mg (equivalent to esomeprazole 20 mg).

excipients :

sugar grains (contains sucrose and starch syrup),

povidone KZ

sodium lauryl sulfate,

Opadry II White 85F28751,

magnesium hydroxycarbonate (heavy magnesium carbonate) methacrylic acid and ethyl acrylate copolymer [1: 1] dispersion 30%,

talc,

macrogol

titanium dioxide (E 171),

polysorbate,

gelatin capsule

Pharmacodynamics

Esomeprazole is the S-isomer of omeprazole and inhibits the secretion of hydrochloric acid in the stomach due to a specific and directed mechanism of action. Specifically inhibits the proton pump of parietal cells. Both omeprazole isomers, R- and S-, have similar pharmacodynamic activity.

Mechanism of action

Esomeprazole is a weak base, therefore, it accumulates and becomes active under conditions of a strongly acidic environment of the secretory tubules of the parietal cells of the gastric mucosa, where it inhibits the activity of the enzyme H +, K + -ATPase. Suppresses both basal and stimulated secretion of hydrochloric acid.

Effect on acid secretion in the stomach

The effect develops within 1 hour after ingestion of 20 mg or 40 mg of esomeprazole. With a repeated intake of 20 mg of esomeprazole once a day for 5 days, the average peak concentration of hydrochloric acid after stimulation with pentagastrin decreases by 90% (on the 5th day of therapy, 6-7 hours after taking the drug).

In patients with gastroesophageal reflux disease (GERD) and the presence of clinical symptoms after daily administration of esomeprazole at a dose of 20 mg or 40 mg for 5 days, the pH of the contents of the stomach above 4.0 was maintained, on average, for 13 and 17 hours, respectively . The proportion of patients taking esomeprazole at a dose of 20 mg / day. in which the pH of the gastric contents exceeded 4.0 for 8, 12 and 16 hours, respectively, was 76%, 54% and 24%, and for esomeprazole 40 mg / day. - 97%, 92% and 56%.

The degree of suppression of acid secretion by esomeprazole is directly dependent on the area under the concentration-time curve.

Therapeutic effect achieved by suppressing acid secretion

The healing of reflux esophagitis, when taking esomeprazole at a dose of 40 mg, occurs in approximately 78% of patients after 4 weeks and in 93% of patients after 8 weeks of therapy. Treatment with esomeprazole in a dose of 20 mg 2 times a day for 1 week in combination with appropriate antibiotics leads to the successful eradication of Helicobacter pylori in 90% of patients.

In case of uncomplicated peptic ulcer after eradication therapy (lasting from 7 to 10-14 days), monotherapy with antisecretory drugs is not required to heal the ulcers and eliminate symptoms.

Other effects associated with suppression of acid secretion

Against the background of therapy with antisecretory drugs, the level of gastrin rises

serum in response to decreased acid secretion.

In some patients, after prolonged therapy with esomeprazole, an increase in the number of enterochromaffin-like (ELC) cells was noted, probably associated with an increase in the level of gastritis in the blood plasma.

With prolonged use of antisecretory drugs, a slight increase in the frequency of formation of glandular cysts of the stomach was noted. These changes are due to physiological changes as a result of prolonged suppression of acid secretion. Cysts are benign and are reversible.

The decrease in the acidity of the gastric contents while taking antisecretory drugs is accompanied by an increase in the content of microbial flora in the stomach, which is present in the gastrointestinal tract (GIT) normally. Therapy with proton pump inhibitors can lead to a slight increase in the risk of infectious diseases of the gastrointestinal tract, for example, caused by bacteria of the genus Salmonella and Campylobacter spp. Esomeprazole is more effective against the healing of stomach ulcers in patients using non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors compared to ranitidine.

Esomeprazole has been shown to be highly effective in the prevention of gastric and duodenal ulcers in patients taking NSAIDs (for patients over 60 and / or with a history of peptic ulcer), including selective COX-2 inhibitors.

Pharmacokinetics

Suction and distribution

Esomeprazole is unstable in an acidic environment, so it is taken orally in the form of enteric capsules containing drug pellets, the shell of which is also resistant to the action of gastric juice. Under in vivo conditions, a small fraction of esomeprazole is converted to the R-isomer. Esomeprazole is rapidly absorbed, reaching maximum plasma concentrations approximately 1-2 hours after ingestion. The absolute bioavailability is 64% after taking a single dose of 40 mg, which increases to 89% against the background of daily intake of esomeprazole once a day. The 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 0.22 l / kg body weight. Communication with plasma proteins - 97%. Eating slows down and reduces the absorption of esomeprazole,

Metabolism and excretion

Esomeprazole is completely metabolized by the liver cytochrome P450 isoenzyme system. Most are metabolized with the participation of the polymorphic isoenzyme CYP2C19, which is responsible for the formation of hydroxy- and demethylated metabolites. The rest of esomeprazole is metabolized by the isoenzyme CYP3A4, which is responsible for the formation of esomeprazole sulfone, the main metabolite in blood plasma. The total plasma clearance after taking a single dose is approximately 17 l / h and 9 l / h after repeated use. The half-life (T1 / 2) is 1.3 hours with prolonged use of the drug once a day. The area under the concentration-time curve (AUC) increases with repeated use. The dose-dependent increase in AUC with repeated use is non-linear due to a decrease in metabolism during the "first passage" through the liver, reduced clearance, probably caused by inhibition of the CYP2C19 isoenzyme by esomeprazole and / or its sulfate-containing metabolite. With a single daily intake, esomeprazole is completely excreted from blood plasma in the interval 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 orally administered dose of esomeprazole is excreted by the kidneys in the form of metabolites, and the rest through the intestines. In urine, less than 1% of unchanged esomeprazole is found.

Pharmacokinetics in individual patient groups

Approximately 2.9 ± 1.5% of the population has reduced CYP2C19 isoenzyme activity. In such patients, the metabolism of esomeprazole is carried out mainly by the CYP3A4 isoenzyme. After taking 40 mg of esomeprazole once a day, the average AUC is about 2 times higher than in patients with reduced CYP2C19 activity. The average values ​​of maximum plasma concentrations (Cmax) increase by approximately 60%.

In elderly patients (71-80 years), the metabolism of esomeprazole does not significantly change.

After a single dose of 40 mg of esomeprazole, the average AUC in women is about 30% higher than in men. Further, with a systematic daily intake of esomeprazole once a day, differences in pharmacokinetics in patients of both sexes were not observed. These features do not affect the dose and method of use of the drug.

The metabolism of esomeprazole may be impaired in people with mild or moderate hepatic impairment. The metabolic rate is reduced with severe violations of the liver, which is accompanied by a twofold increase in AUC. Therefore, the maximum daily dose of esomeprazole in these patients is 20 mg. A study in patients with reduced renal function was not conducted. Since it is not the esomeprazole itself that is excreted through the kidneys, but its metabolites, the metabolism of esomeprazole in these patients does not change.

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

Gastroesophageal Reflux Disease (GERD):

• treatment of erosive reflux esophagitis;
• long-term supportive treatment after healing of erosive reflux esophagitis in order to prevent relapse;
• symptomatic treatment of GERD.

Peptic ulcer of the stomach and duodenum.

As part of combination antibiotic therapy to eradicate Helicobacter pylori:

• duodenal ulcer associated with Helicobacter pylori,
• prevention of relapse of peptic ulcer associated with Helicobacter pylori.

Patients taking long-term non-steroidal anti-inflammatory drugs (NSAIDs):

• healing of stomach ulcers associated with NSAIDs;
• prevention of gastric and duodenal ulcers associated with NSAIDs in patients at risk.

Long-term prophylaxis of relapses of repeated bleeding from peptic ulcers (after intravenous use of drugs that lower the secretion of gastric glands);

Zollinger-Ellison syndrome and other conditions characterized by increased gastric secretion, including idiopathic hypersecretion.

The use of the drug Emanera during pregnancy is possible only if the expected benefit to the mother outweighs the possible risk to the fetus, because insufficient data on the use of esomeprazole in pregnant women.

In epidemiological studies during the use of the racemic mixture of omeprazole, fetotoxic effects or impaired fetal development were not detected.

In studies with esomeprazole in animals, there was no direct or indirect negative effect on the development of the embryo or fetus; Neither a direct or indirect negative effect on the course of pregnancy, childbirth and the postnatal period of the newborn was revealed.

It is currently unknown whether esomeprazole with breast milk is excreted, therefore, the drug Emanera should not be used during breast-feeding.

• hypersensitivity to esomeprazole, substituted benzimidazoles or components of the drug Emanera;
• concomitant use with atazanavir and nelfinavir;
• hereditary fructose intolerance;
• glucose-galactose malabsorption syndrome or sucrose-isomaltase deficiency;
• children under 12 years of age (there is no data on efficacy and safety) and over 12 years old for other indications, except gastroesophageal reflux disease (GERD).

Precautions: severe renal failure (limited experience).

In each group, unwanted effects are presented in decreasing order of severity.

From the nervous system: often - headache; infrequently - insomnia, dizziness, paresthesia, drowsiness; rarely - depression, agitation, confusion; very rarely - hallucinations, aggressive behavior.

From the respiratory system: rarely - bronchospasm.

From the digestive system: often - abdominal pain, constipation, diarrhea, flatulence, nausea, vomiting; infrequently - dryness of the oral mucosa, increased activity of liver enzymes; rarely - stomatitis, gastrointestinal candidiasis, hepatitis (with or without jaundice); very rarely - liver failure, hepatic encephalopathy in patients with a history of liver disease.

From the urinary system: very rarely - interstitial nephritis.

From the reproductive system: very rarely - gynecomastia.

From the musculoskeletal system: rarely - arthralgia, myalgia; very rarely - muscle weakness.

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

From the hemopoietic organs: rarely - leukopenia, thrombocytopenia; very rarely - agranulocytosis, pancytopenia.

From the sensory organs: infrequently - blurred vision; rarely, a change in taste.

Allergic reactions: rarely - hypersensitivity reactions (e.g. fever, angioedema, anaphylactic reaction / anaphylactic shock).

Laboratory data: rarely - hyponatremia.

Other: infrequently - peripheral edema; rarely sweating; very rarely - weakness (malaise).

The effect of esomeprazole on the pharmacokinetics of other drugs

Medicines whose absorption depends on the pH level. A decrease in the acidity level of gastric juice during treatment with esomeprazole can lead to a change in the absorption of drugs, the absorption of which depends on the acidity of the medium. Like antacids and other drugs that reduce the secretion of gastric glands, esomeprazole reduces the absorption of ketoconazole and itraconazole. The simultaneous use of omeprazole (at a dose of 40 mg once a day) and some antiretroviral drugs (atazanavir - at a dose of 300 mg / ritonavir - at a dose of 100 mg) in healthy volunteers is accompanied by a pronounced decrease in the exposure of atazanavir (AUC, C _max and C _minin blood plasma decreased by about 75%). An increase in the dose of atazanavir to 400 mg did not compensate for this decrease in exposure. Proton pump inhibitors, incl. esomeprazole should not be taken concomitantly with atazanavir.

Drugs metabolized by CYP2C19. Esomeprazole inhibits CYP2C19, the main isoenzyme of esomeprazole metabolism. Thus, with the simultaneous use of esomeprazole with drugs in the metabolism of which the CYP2C19 isoenzyme is involved, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, the concentration of these drugs in blood plasma may increase and, accordingly, a reduction in their dose may be required. This is especially necessary to consider when prescribing the drug Emanera in demand mode. So, with the simultaneous use of 30 mg of esomeprazole, the clearance of diazepam (substrate CYP2C19) is reduced by 45%.

The simultaneous use of 40 mg of esomeprazole in patients with epilepsy leads to a decrease in the concentration of phenytoin in blood plasma by 13%. It is recommended to control the concentration of phenytoin in blood plasma at the beginning of therapy and with the abolition of esomeprazole.

When applying 40 mg of omeprazole, C _max and AUC of voriconazole (substrate CYP2C19) increase by 15 and 41%, respectively.

Esomeprazole does not cause a clinically significant change in the pharmacokinetics of amoxicillin and quinidine.

The bleeding time while taking warfarin and 40 mg of esomeprazole remains within acceptable limits. However, several cases of a clinically significant increase in MHO have been reported. It is recommended that MHO be monitored in cases where the use of esomeprazole begins or stops during therapy with warfarin or other coumarin derivatives.

The simultaneous use of 40 mg of esomeprazole with cisapride leads to an increase in the pharmacokinetic parameters of cisapride: AUC by 32% and T _1/2  by 31%, however, C _max does not significantly change. The slight prolongation of the QT interval on the ECG, which is observed with monotherapy with cisapride, did not increase with the addition of esomeprazole.

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

The effect of drugs on the pharmacokinetics of esomeprazole

Esomeprazole is metabolized by the enzymes CYP2C19 and CYP3A4. With the simultaneous use of esomeprazole with clarithromycin (at a dose of 500 mg 2 times a day) (CYP3A4 inhibitor), the AUC value of esomeprazole increases by 2 times.

The simultaneous use of esomeprazole and the combined inhibitor of CYP2C19 and CYP3A4 may be accompanied by an increase in the AUC of esomeprazole by more than 2 times. CYP2C19 and CYP3A4 inhibitors, such as voriconazole, increased AUC of esomeprazole by 280%. Usually, in such situations, a dose change of esomeprazole is not required, but in patients with significant impaired liver function or, if necessary, long-term therapy, the question of reducing the dose of esomeprazole should be decided.

Inside, without chewing, washing down with a small amount of liquid. For patients with difficulty swallowing, pour the contents of the capsules into half a glass of still water, stir and drink immediately or within 30 minutes. Then refill the glass halfway with water, rinse the walls of the glass and drink. Do not mix the drug with other liquids, as this can lead to the dissolution of the pellet shell. Pellets should not be chewed or crushed.

For patients who cannot swallow on their own, the contents of the capsules should be dissolved in still water and esomeprazole is administered via a nasogastric tube. It is necessary to check the compliance of the syringe for the introduction of the drug and the probe.

Adults and teenagers over 12 years old

Gastroesophageal Reflux Disease (GERD):

- Erosive reflux esophagitis (treatment): 40 mg 1 time per day for 4 weeks. If after the first course of therapy, the healing of esophagitis does not occur or symptoms persist, an additional 4-week course of treatment with esomeprazole is recommended,

- Long-term supportive treatment after healing of erosive reflux esophagitis to prevent relapse: 20 mg 1 time per day.

- Symptomatic treatment of GERD: 20 mg once daily for patients without esophagitis. If, after 4 weeks of therapy, symptom control cannot be achieved, a repeated examination of the patient is necessary. After the symptoms have been eliminated, you can continue to take Emanera on demand, i.e. take 20 mg of the drug 1 time per day if symptoms occur. Patients taking NSAIDs, at risk of developing stomach ulcers or duodenal ulcers, are not recommended treatment on demand.

Adult patients

- Peptic ulcer of the stomach and duodenum.

- As part of combination antibiotic therapy to eradicate Helicobacter pylori

- Duodenal ulcer associated with Helicobacter pylori and prevention of relapse of peptic ulcer associated with Helicobacter pylori: Helicobacter pylori combined eradication therapy includes: Emanera® 20 mg, amoxicillin 1 g and clarithromycin 500 mg. All drugs are taken 2 times a day for 7-14 days.

- Patients taking long-term non-steroidal anti-inflammatory drugs (NSAIDs):

- Healing of gastric ulcers associated with NSAIDs: 20 mg or 40 mg 1 time per day for 4-8 weeks.

- Prevention of gastric and duodenal ulcers associated with NSAIDs in patients at risk: drug Emanera® 20 mg or 40 mg once a day.

- Long-term prophylaxis of relapses of repeated bleeding from peptic ulcers (after intravenous use of drugs that lower the secretion of the gastric glands): Emanera® 40 mg 1 time per day for 4 weeks after the start of intravenous prevention of repeated bleeding.

- Zollinger-Ellison syndrome and other conditions characterized by increased

gastric secretion, including idiopathic hypersecretion: initial dose

Emanera drug 40 mg 2 times a day. The dose of the drug and the duration of treatment are selected individually depending on the clinical picture of the disease.

The disease in most patients is controlled by taking the drug in a dose of 80 mg to 160 mg per day. If it is necessary to use the drug Emanera® over 80 mg per day, the daily dose is divided into two doses.

Impaired renal function

In patients with impaired renal function, a dose change is not required. Experience with esomeprazole in patients with severe renal failure is limited; in this regard, caution should be exercised when prescribing the drug to such patients.

Impaired liver function

Patients with mild or moderate hepatic impairment are not required to change the dose. In severe liver failure, the maximum daily dose should not exceed 20 mg.

Elderly patients

Elderly patients do not need dose adjustment.

The introduction of the drug through a nasogastric tube

When prescribing the drug through a nasogastric tube:

1. Open the capsule and pour the contents of the capsule into a special syringe. Add 25 ml of drinking water and approximately 5 ml of air to the syringe. For some probes, it may be necessary to dilute the drug in 50 ml of drinking water in order to prevent clogging of the probe with the pellets contained in the capsule.
2. After adding water, immediately shake the syringe until a suspension is obtained.
3. Make sure that the tip is not clogged (by pushing the plunger slightly while holding the syringe with the tip up).
4. Insert the tip of the syringe into the probe while continuing to hold it upward.
5. Shake the syringe and turn it upside down. Immediately inject 5-10 ml of the dissolved drug into the probe. After administering the solution, return the syringe to its previous position and shake (the syringe must be held tip up to avoid clogging the tip).
6. Re-lower the syringe with the tip down and introduce another 5-10 ml of the solution into the probe. Repeat the procedure until the syringe is empty. If a part of the preparation remains as a precipitate in a syringe: fill the syringe with 25 ml of water and 5 ml of air and repeat the procedures described in paragraphs 5 and 6. For some probes, 50 ml of drinking water may be needed for this purpose.

To date, cases of overdose of the drug Emanera are not described. Intake of esomeprazole at a dose of 280 mg was accompanied by general weakness and gastrointestinal symptoms.

A single oral administration of 80 mg of esomeprazole was not accompanied by any symptoms. A specific antidote does not exist. Esomeprazole is actively associated with plasma proteins, so hemodialysis is ineffective.

Treatment: in case of overdose, symptomatic therapy should be carried out.

In case of disturbing symptoms (for example, such as significant spontaneous weight loss, repeated vomiting, dysphagia, vomiting with blood or melena), as well as with suspicion or detection of gastric ulcers, it is necessary to exclude a malignant neoplasm, since the use of Emaner can reduce the severity of symptoms and delay the diagnosis.

Patients who have been taking Emanera for a long time (especially more than a year) should be under regular medical supervision.

Patients taking the drug on demand should be informed about the need to see a doctor if the nature of the symptoms changes.

Given the fluctuations in the concentration of esomeprazole in blood plasma when using the drug in on-demand regimen, interactions with other drugs should be considered. When using esomeprazole to eradicate Helicobacter pylori, the possible interaction between the components of the triple therapy should be considered. Clarithromycin is a potent inhibitor of CYP3A4, therefore, contraindications and drug interactions of clarithromycin should be considered when administering triple therapy to patients simultaneously taking drugs metabolized by CYP3A4, such as cisapride.

Emanera contains sucrose, therefore its use is contraindicated in patients with hereditary fructose intolerance, glucose-galactose malabsorption syndrome or sucrose-isomaltase deficiency.

Influence on the ability to drive vehicles and other complex mechanisms. The drug Emanera does not affect driving and working with other technical devices, which requires an increased concentration of attention and speed of psychomotor reactions.