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Active ingredients
Esomeprazole
Release form
Capsules
Composition
Active ingredient: Esomeprazole Magnesium 40 mg. Excipients: sugar krupka (contains sucrose and starch syrup) - 71.16 mg; Povidone K30 - 15 mg; sodium lauryl sulfate - 1.8 mg. Shell pellets: Opadry II white 85F28751 (polyvinyl alcohol - 18.752 mg; titanium dioxide (E171) - 11.72 mg; macrogol 3000 - 9.47 mg; talc - 6.938 mg) - 46.88 mg; magnesium hydroxycarbonate (magnesium carbonate heavy) - 6 mg; methacrylic acid and ethyl acrylate copolymer (1: 1); dispersion 30% * - 254.98 mg; talc - 23.85 mg; macrogol 6000 - 7.65 mg; titanium dioxide (E171) - 7.65 mg; polysorbate 80 - 3.44 mg. Empty gelatin capsules case: iron dye red oxide (E172) - 0.114 mg; titanium dioxide (E171) - 0.458 mg; gelatin ** - 45.028 mg. Lid: iron dye red oxide (E172) - 0.076 mg; titanium dioxide (E171) - 0.055 mg; gelatin ** - 30.019 mg. * dispersion Eudragit L30D contains, in addition to methacrylic acid, copolymer ethyl acrylate and water, also sodium lauryl sulfate (0.7% based on the solid in the dispersion) and polysorbate 80 (2.3% based on the solid in the dispersion) as emulsifiers * * contains an average of 14.5% water (loss in weight during drying)
Pharmacological effect
Proton pump inhibitor
Pharmacokinetics
Absorption and distribution Esomeprazole is unstable in an acidic environment, therefore, is taken orally in the form of enteric capsules containing pellets of the drug, the shell of which is also resistant to the action of gastric juice. In vivo, a small portion of the esomeprazole is converted to the R isomer. Esomeprazole is rapidly absorbed, reaching Cmax in the blood plasma approximately 1–2 hours after ingestion. Absolute bioavailability is 64% after a single dose of 40 mg and increases to 89% on the background of daily intake of esomeprazole 1 time per day. Bioavailability for esomeprazole at a dose of 20 mg is 50 and 68%, respectively. Vss in healthy volunteers is approximately 0.22 l / kg. Communication with plasma proteins - 97%. Eating slows down and reduces the absorption of esomeprazole, which has no significant clinical significance. Metabolism and elimination Esomeprazole is completely metabolized with the participation of the cytochrome P450 isoenzyme system in the liver. Most of the metabolized with the participation of the polymorphic isoenzyme CYP2C19, which is responsible for the formation of hydroxy- and demethylated metabolites.The rest of the esomeprazole is metabolized by the CYP3A4 isoenzyme, which is responsible for the formation of the sulfone of esomeprazole, the main metabolite in the blood plasma. Total plasma clearance after a single dose is approximately 17 and 9 l / h after repeated administration. T1 / 2 is 1.3 hours with long-term use of the drug 1 time per day. 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, a decrease in clearance, probably caused by inhibition of the CYP2C19 isoenzyme by esomeprazole and / or its sulfa-containing metabolite. With a single daily dose, esomeprazole is completely eliminated from the blood plasma during the interval between doses. Esomeprazole does not accumulate. The major metabolites of esomeprazole do not affect the secretion of hydrochloric acid in the stomach. Almost 80% of the orally administered esomeprazole dose is excreted by the kidneys as metabolites, and the rest through the intestines. Less than 1% of unchanged esomeprazole is found in the urine. Pharmacokinetics in certain groups of patients Approximately in (2.9 ± 1.5)% of the population, the activity of the CYP2C19 isoenzyme is reduced. In these patients, the metabolism of esomeprazole is carried out mainly by CYP3A4 isoenzyme. After repeated administration of esomeprazole at a dose of 40 mg 1 time per day, the average AUC value is about 2 times higher than in patients with reduced CYP2C19 activity. The mean value of plasma Cmax increases by approximately 60%. In elderly patients (71–80 years), the metabolism of esomeprazole does not change significantly. After a single dose of 40 mg of esomeprazole, the average AUC value in women is about 30% higher than in men. Subsequently, with systematic daily intake of esomeprazole 1 time per day, no differences in pharmacokinetics were observed in patients of both sexes. These features do not affect the dose and method of use of the drug. Esomeprazole metabolism may be impaired in people with mild or moderate hepatic impairment. The metabolic rate is reduced in severe impaired liver function, which is accompanied by a twofold increase in AUC. Therefore, the maximum daily dose of esomeprazole in these patients is 20 mg. The study in patients with reduced kidney function was not conducted.Since not the esomeprazole itself but its metabolites are eliminated through the kidneys, the metabolism of esomeprazole in these patients does not change. After repeated administration of 20 and 40 mg of esomeprazole, the levels of AUC and the time to reach Cmax in children aged 12–18 years and adults were the same.
Indications
Gastroesophageal reflux disease (GERD): - treatment of erosive reflux esophagitis; - long-term maintenance treatment after healing of erosive reflux esophagitis in order to prevent recurrence; - symptomatic treatment of GERD; peptic ulcer and duodenal ulcer; in combination antibacterial therapy for the eradication of Helicobacter pylori: - duodenal ulcer associated with Helicobacter pylori; - prevention of recurrence of peptic ulcers associated with Helicobacter pylori; patients who take NSAIDs for a long time: - the healing of gastric ulcers associated with taking NSAIDs; - prevention of gastric and duodenal ulcers associated with the intake of NSAIDs in patients at risk; long-term prevention of recurrence of repeated bleeding from peptic ulcers (after i / v use of drugs that lower the secretion of gastric glands); Zollinger-Ellison syndrome and other conditions characterized by increased gastric secretion, including idiopathic hypersecretion.
Contraindications
Hypersensitivity to esomeprazole, substituted benzimidazoles, or drug components; simultaneous administration with atazanavir and nelfinavir; hereditary intolerance to fructose; glucose-galactose malabsorption syndrome or sucrose-isomaltose deficiency; Children up to 12 years old (no data on efficacy and safety) and over 12 years old - for other indications, except gastroesophageal reflux disease (GERD). With care: a heavy renal failure (experience of use is limited).
Use during pregnancy and lactation
Use of the drug Emaner during pregnancy is possible only if the expected benefit to the mother exceeds the possible risk to the fetus, insufficient data on the use of esomeprazole in pregnant women. In epidemiological studies during the use of the racemic mixture of omeprazole, no fetotoxic effects or impaired fetal development were detected.In studies with esomeprazole in animals, no direct or indirect negative effect on the development of the embryo or fetus was detected; also, no direct or indirect negative effect on the course of pregnancy, childbirth and the postnatal period of the newborn was revealed. At present, it is not known whether esomeprazole is excreted in breast milk; therefore, Emaner should not be used during breastfeeding.
Dosage and administration
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 non-carbonated water, stir and drink immediately or within 30 minutes. Then re-fill the glass with water by half, rinse the walls of the glass and drink. Do not mix the drug with other liquids, because This may lead to the dissolution of the pellet containment shell. Pellets should not be chewed or crushed. Patients who cannot swallow on their own should dissolve the contents of the capsules in non-carbonated water and inject esomeprazole through a nasogastric tube. It is necessary to check the compliance of the syringe for the injection and the probe. Instructions on the preparation and administration of the drug through a nasogastric tube are provided in the subsection "Dosing the drug through a nasogastric tube". Adults and teenagers older than 12 years 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 maintenance treatment after healing of erosive reflux esophagitis to prevent relapse: 20 mg 1 time per day. - Symptomatic treatment of GERD: 20 mg 1 time per day - for patients without esophagitis. If after 4 weeks. therapy could not achieve control of symptoms, it is necessary to re-examine the patient. After the symptoms are eliminated, you can continue taking the drug Emaner on demand, i.e. take 20 mg of the drug 1 time per day if symptoms occur. Patients taking NSAIDs that are at risk of developing gastric or duodenal ulcers are not recommended treatment on demand.Adult patients with stomach ulcer and duodenal ulcer in part of combination antibiotic therapy to eradicate Helicobacter pylori: - Duodenal ulcer associated with Helicobacter pylori and prevention of relapse of peptic ulcers associated with Helicobacter pylori (in the Helicobacter combined eradication therapy pylori include: Emanera 20 mg, amoxicillin 1 g and clarithromycin 500 mg). All drugs are taken 2 times a day, 7-14 days. Patients who have been taking NSAIDs for a long time: - Healing of gastric ulcers associated with taking NSAIDs: 20 mg or 40 mg 1 time per day for 4–8 weeks. - Prevention of gastric and duodenal ulcers associated with taking NSAIDs in patients at risk: Emanera 20 mg or 40 mg once a day. Long-term prevention of recurrence of repeated bleeding from peptic ulcers (after intravenous administration of drugs that lower the secretion of gastric glands): Emanera 40 mg once a day for 4 weeks. after started in / in the prevention of recurrent bleeding. Zollinger-Ellison syndrome and other conditions characterized by increased gastric secretion, including idiopathic hypersecretion: the initial dose of the drug Emaner 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 to 160 mg / day. If necessary, the use of the drug Emaner more than 80 mg / day, the daily dose is divided into two doses. Impaired renal function. Patients with impaired renal function dose change is not required. Experience with the use of esomeprazole in patients with severe renal insufficiency is limited; In this regard, in the appointment of the drug in such patients should be careful. Liver dysfunction. 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 dose adjustment is not required. Injection of the drug through a nasogastric tube When prescribing a drug through a nasogastric tube, it is necessary to: 1. Open the capsule and pour the contents of the capsule into a special syringe.Add 25 ml of drinking water and about 5 ml of air to the syringe. Some probes may require dilution of the product in 50 ml of drinking water in order to prevent the pellets contained in the capsule from clogging the probe. 2. After adding water, immediately shake the syringe to obtain a suspension. 3. Make sure that the tip is not clogged (slightly pressing down on the piston, holding the syringe in position with the tip up). 4. Insert the tip of the syringe into the probe, continuing to hold it up. 5. Shake the syringe and tip it upside down. Immediately introduce 5–10 ml of the dissolved drug into the probe. After the introduction of the solution, return the syringe to its previous position and shake (the syringe should be kept tip up to avoid clogging the tip). 6. Again, lower the syringe tip down and inject another 5-10 ml of solution into the probe. Repeat the procedure until the syringe is empty. 7. In case of residual part of the preparation as a precipitate in the 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.
Side effects
From the nervous system: often - headache; infrequently - insomnia, dizziness, paresthesias, drowsiness; rarely - depression, agitation, confusion; very rarely - hallucinations, aggressive behavior. On the part of the respiratory system: rarely - bronchospasm. On the part of 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. On the part of the urinary system: very rarely - interstitial nephritis. Reproductive system: very rarely - gynecomastia. On the part of the musculoskeletal system: rarely - arthralgia, myalgia; very rarely - muscle weakness. On the part of the skin: infrequently - dermatitis, skin rash, pruritus, urticaria; rarely - alopecia, photosensitivity; very rarely - erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.From the side of blood-forming organs: rarely - leukopenia, thrombocytopenia; very rarely - agranulocytosis, pancytopenia. On the part of the senses: infrequently - blurred vision; rarely - a change in taste. Allergic reactions: rarely hypersensitivity reactions (for example, fever, angioedema, anaphylactic reaction / anaphylactic shock). Laboratory data: rarely - hyponatremia; very rarely - hypomagnesaemia, hypocalcemia due to severe hypomagnesemia, hypokalemia due to severe hypomagnemia. Other: infrequent - peripheral edema; rarely - sweating; very rarely - weakness (malaise).
Overdose
To date, cases of overdose of the drug Emaner not described. Ingestion of esomeprazole at a dose of 280 mg was accompanied by general weakness and symptoms of the gastrointestinal tract. A single intake 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
Interaction with other drugs
Drugs, the absorption of which depends on the pH level. Reduced secretion of hydrochloric acid in the stomach during treatment with esomeprazole and other proton pump inhibitors may lead to changes in the absorption of drugs, the absorption of which depends on the acidity of the medium. Like antacids and other drugs that reduce gastric acidity, esomeprazole may reduce the absorption of ketoconazole, itraconazole and erlotinib, and increase the absorption of drugs such as digoxin. The simultaneous administration of omeprazole in a dose of 20 mg once a day and digoxin increases the bioavailability of digoxin by 10% (the bioavailability of digoxin increased by up to 30% in 2 out of 10 patients). It is known about the interaction of omeprazole with some antiretroviral drugs. The mechanism and clinical significance of these interactions are not always known. Reducing the acidity of gastric juice during therapy with omeprazole may affect the absorption of antiretroviral drugs. Interaction at the level of an isoenzyme CYP2C19 is also possible. During therapy with omeprazole, a decrease in the serum concentration of certain antiretroviral drugs (atazanavir and nelfinavir) has been observed.Therefore, simultaneous use is not recommended. The simultaneous use of omeprazole (40 mg once daily) with atazanavir 300 mg / ritonavir 100 mg in healthy volunteers is accompanied by a marked decrease in the exposure to atazanavir (AUC, Cmax and Cmin in plasma decreased by about 75%). Increasing the dose of atazanavir to 400 mg did not compensate for the effects of omeprazole on the bioavailability of atazanavir. With simultaneous use of omeprazole with saquinavir, serum concentration of saquinavir increases. Given the similar pharmacokinetic and pharmacodynamic properties of omeprazole and esomeprazole, the simultaneous use of esomeprazole with antiretroviral drugs such as atazanavir and nelfinavir is not recommended. CYP2C19 metabolized drugs. Esomeprazole inhibits CYP2C19, the main isoenzyme of the metabolism of esomeprazole. Thus, with simultaneous use of esomeprazole with drugs whose metabolism involves the CYP2C19 isoenzyme, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., the plasma concentration of these drugs may increase and, accordingly, their dose reduction . This is especially necessary to consider when prescribing the drug Emaner in the mode of necessity. So, with simultaneous use with 30 mg of esomeprazole, the clearance of diazepam (substrate of CYP2C19 isoenzyme) is reduced by 45%. The simultaneous use of esomeprazole at a dose of 40 mg leads to an increase in the concentration of phenytoin in the blood plasma of patients with epilepsy by 13%. It is recommended to control the concentration of phenytoin in the blood plasma at the beginning of therapy with esomeprazole and in case of its cancellation. With the use of omeprazole in a dose of 40 mg, the Cmax and AUC of voriconazole (substrate of CYP2C19 isoenzyme) increases by 15 and 41%, respectively. The coagulation time while simultaneously taking warfarin and esomeprazole at a dose of 40 mg remains within acceptable limits. However, several cases of a clinically significant increase in the INR index have been reported. It is recommended to control INR at the beginning and at the end of the simultaneous use of esomeprazole and warfarin or other coumarin derivatives. The use of omeprazole at a dose of 40 mg led to an increase in Cmax and AUC of Cilostazol by 18 and 26%, respectively; for one of the active metabolites of Cilostazol, the increase was 29 and 69%, respectively.The simultaneous use of esomeprazole in a dose of 40 mg with cisapride leads to an increase in the values of pharmacokinetic parameters of cisapride in healthy volunteers: AUC - by 32% and T1 / 2 - by 31%, however, Cmax does not change significantly. A slight lengthening of the QT interval on the ECG, which is observed with cisapride monotherapy, did not increase with the addition of esomeprazole. Some patients noted an increase in the concentration of methotrexate in the serum against the background of simultaneous use with proton pump inhibitors. When using high doses of methotrexate, the possibility of temporary withdrawal of esomeprazole should be considered. Esomeprazole does not cause clinically significant changes in the pharmacokinetics of amoxicillin and quinidine. Simultaneous short-term use of esomeprazole and naproxen or rofecoxib showed no clinically significant pharmacokinetic interaction. In a clinical study, the interaction with the use of clopidogrel (300 mg — loading dose, then 75 mg / day) with omeprazole (80 mg) simultaneously, at the same time for 5 days was studied. The activity of the thiol metabolite (active metabolite) of clopidogrel was reduced by 46% (1st day of therapy) and 42% (5th day of therapy), while taking clopidogrel and omeprazole at the same time. When clopidogrel and omeprazole were taken at the same time, the mean suppression of platelet aggregation (IPA) was reduced by 47% (during 24 hours of therapy) and 30% (5th day of therapy). According to the results of another study: omeprazole, when used with clopidogrel, not simultaneously, at different times, has no inhibitory effect on the CYP2C19 isoenzyme. The studies have documented conflicting data on the clinical manifestations of clopidogrel interaction with major cardiovascular events. With simultaneous use with tacrolimus, an increase in serum tacrolimus concentrations is possible. Effect of drugs on the pharmacokinetics of esomeprazole The isomers of CYP2C19 and CYP3A4 are involved in the metabolism of esomeprazole. With simultaneous use of esomeprazole with clarithromycin (500 mg 2 times a day) (inhibitor of the isoenzyme CYP3A4), the AUC value of esomeprazole increases by 2 times. The simultaneous use of esomeprazole and the combined inhibitor of CYP2C19 and CYP3A4 isoenzymes, for example, voriconazole, may be accompanied by an increase in the AUC of esomeprazole by more than 2 times. Usually in such situations, no change in the dose of esomeprazole is required.In patients with severely impaired liver function or, if necessary, long-term therapy, the question of reducing the dose of esomeprazole should be resolved. Drugs that induce CYP2C19 and CYP3A4 isoenzymes, such as rifampicin and Hypericum perforatum drugs, when used simultaneously with esomeprazole can lead to a decrease in the concentration of esomeprazole in the blood plasma by accelerating the metabolism of esomeprazole.
special instructions
If anxious symptoms appear (such as significant spontaneous weight loss, repeated vomiting, dysphagia, vomiting with blood or melena), as well as suspected or detected gastric ulcers, it is necessary to exclude a malignant neoplasm, because the use of Emanera can reduce the severity of symptoms and delay making a diagnosis. Patients who have been taking Emaner for a long time (especially for more than a year) should be under regular medical supervision. Patients taking the drug on demand should be informed of the need to see a doctor when symptoms change. Given the fluctuations in the concentration of esomeprazole in the blood plasma when using the drug in the mode on demand, interactions with other drugs should be considered (see "Interaction"). When using esomeprazole to eradicate Helicobacter pylori, consideration should be given to the possible interaction between the components of triple therapy. Clarithromycin is a potent inhibitor of CYP3A4, therefore, contraindications and drug interaction of clarithromycin should be considered when prescribing triple therapy to patients who are simultaneously taking drugs that are metabolized by CYP3A4, such as cisapride. The drug Emaner contains sucrose, so its use is contraindicated in patients with hereditary fructose intolerance, glucose-galactose malabsorption syndrome or sucrose-isomaltase deficiency. Impact on the ability to drive vehicles and other complex mechanisms. The drug Emanera does not affect the management of vehicles and work with other technical devices, requiring high concentration of attention and speed of psychomotor reactions