EMANERA
Directions for use and doses
Orally, without chewing, 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 fill the glass halfway with water, rinse the sides of the glass and drink.
The drug should not be mixed with other liquids, because this may lead to the dissolution of the pellet's protective coating. Pellets should not be chewed or crushed.
For patients who are unable to swallow on their own, the contents of the capsules should be dissolved in still water and esomeprazole administered through a nasogastric tube. It is necessary to check the compliance of the syringe for administering the drug and the probe. Instructions for preparing and administering the drug through a nasogastric tube are given in the subsection “Administration of the drug through a nasogastric tube.”
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, 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 of therapy it is not possible to achieve control of symptoms, it is necessary to re-examine the patient. After eliminating the symptoms, you can continue taking Emanera “on demand”, i.e. take 20 mg of the drug once a day if symptoms occur. For patients taking NSAIDs at risk of developing gastric or duodenal ulcers, on-demand treatment is not recommended.
Adult patients
— Peptic ulcer of the stomach and duodenum.
— As part of combination antibacterial therapy for the eradication of Helicobacter pylori
— Duodenal ulcer associated with Helicobacter pylori and prevention of relapse of peptic ulcer associated with Helicobacter pylori:
Combination eradication therapy for Helicobacter pylori includes: Emanera 20 mg, amoxicillin 1 g and clarithromycin 500 mg. All medications are taken 2 times a day for 7-14 days.
— Patients taking non-steroidal anti-inflammatory drugs (NSAIDs) for a long time:
- Healing of stomach ulcers associated with taking NSAIDs: 20 mg or 40 mg once a 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 1 per day.
— Long-term prevention of recurrent bleeding from peptic ulcers (after intravenous use of drugs that reduce the secretion of gastric glands): Emanera 40 mg once a day
day for 4 weeks after intravenous prevention of recurrent bleeding was started.
— Zollinger-Ellison syndrome and other conditions characterized by increased gastric secretion, including idiopathic hypersecretion: the initial dose of Emanera is 40 mg 2 times a day. The dose of the drug and 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.
Renal dysfunction
Patients with impaired renal function do not require dose changes. Experience with esomeprazole in patients with severe renal impairment is limited; therefore, caution should be exercised when prescribing the drug to such patients. Liver dysfunction
Patients with mild or moderate liver dysfunction do not require dose changes. In severe liver failure, the maximum daily dose should not exceed 20 mg.
Elderly patients
Elderly patients do not require dose adjustment.
Administration 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 pellets contained in the capsule.
2. After adding water, immediately shake the syringe to obtain a suspension.
3. Make sure the tip is not clogged (press the plunger slightly while holding the syringe in the tip-up position).
4. Insert the tip of the syringe into the probe, continuing to keep it pointed upward.
5. Shake the syringe and turn it upside down. Immediately inject 5-10 ml of the dissolved drug into the tube. After injecting the solution, return the syringe to its original position and shake (the syringe should be held with the tip up to avoid clogging of the tip).
6. Lower the syringe again with the tip down and inject another 5-10 ml of solution into the probe. Repeat the procedure until the syringe is empty.
7. If some of the drug remains as sediment in the syringe: fill the syringe with 25 ml of water and 5 ml of air and repeat the procedures described in points 5 and 6. For some probes, 50 ml of drinking water may be needed for this purpose.
Emanera®
Effect of esomeprazole on the pharmacokinetics of other drugs
Drugs whose absorption depends on pH levels
A decrease in the secretion of hydrochloric acid in the stomach during treatment with esomeprazole and other PPIs can lead to changes in the absorption of drugs, the absorption of which depends on the level of acidity of the environment. Like antacids and other drugs that reduce gastric acidity, esomeprazole may reduce the absorption of ketoconazole, itraconazole and erlotinib.
and increasing the absorption of drugs such as
digoxin.
Concomitant use of omeprazole 20 mg once daily and digoxin
increases the bioavailability
of digoxin
by 10% (bioavailability
of digoxin
increased by up to 30% in two out of ten patients).
Omeprazole is known to interact with some antiviral drugs.
The mechanism and clinical significance of these interactions are not always known.
A decrease in gastric acidity during omeprazole therapy may affect the absorption of antiviral drugs.
Interaction at the level of the CYP2C19 isoenzyme is also possible.
During therapy with omeprazole, there is a decrease in the serum concentrations of some antiviral drugs (atazanavir and nelfinavir).
Therefore, simultaneous use is contraindicated.
Concomitant 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 bioavailability of atazanavir (AUC, Cmax and minimum concentration [Cmin] in plasma decreased by approximately 75%).
Increasing the atazanavir
to 400 mg did not compensate for the effect of omeprazole on the bioavailability
of atazanavir.
When omeprazole is used concomitantly with saquinavir
of saquinavir
increases .
Given the similar pharmacokinetic and pharmacodynamic properties of omeprazole and esomeprazole, the simultaneous use of esomeprazole with antiviral drugs such as atazanavir and nelfinavir,
contraindicated.
Drugs metabolized by the
CYP2C19 isoenzyme
CYP2C19 of esomeprazole metabolism. Thus, with simultaneous use of esomeprazole with drugs whose metabolism involves the CYP2C19 isoenzyme, such as diazepam, citalopram, imipramine, clomipramine, phenytoin
etc., the concentration of these drugs in the blood plasma may increase and, accordingly, a reduction in their dose may be required.
This especially needs to be taken into account when prescribing Emanera® in the on-demand mode. Thus, when used simultaneously with 30 mg of esomeprazole, the clearance of diazepam
(CYP2C19 isoenzyme substrate) by 45%.
Concomitant use of esomeprazole at a dose of 40 mg leads to an increase in phenytoin
in the blood plasma of patients with epilepsy by 13%. It is recommended to monitor plasma concentrations of phenytoin when initiating esomeprazole therapy and when discontinuing it.
When using omeprazole at a dose of 40 mg, the Cmax and AUC of voriconazole
(CYP2C19 isoenzyme substrate) by 15% and 41%, respectively.
Coagulation time with simultaneous long-term use of warfarin
and esomeprazole at a dose of 40 mg remains within acceptable limits.
However, a few cases of clinically significant increases in the international normalized ratio (INR) have been reported. It is recommended to monitor the INR at the beginning and at the end of concomitant 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.
Concomitant use of esomeprazole 40 mg with cisapride
leads to an increase in the values of the pharmacokinetic parameters of cisapride in healthy volunteers: AUC - by 32% and T1/2 - by 31%, but Cmax does not change significantly. The slight prolongation of the QT interval on the ECG, which is observed with cisapride monotherapy, was not increased by the addition of esomeprazole.
Some patients experienced increased concentrations of methotrexate
in blood serum during simultaneous use with PPIs. 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.
Concomitant short-term use of esomeprazole and naproxen or rofecoxib
did not reveal a clinically significant pharmacokinetic interaction. Results obtained from studies in healthy volunteers demonstrated a pharmacokinetic/pharmacodynamic interaction between clopidogrel (loading dose 300 mg/maintenance dose 75 mg per day) and esomeprazole (40 mg per day when administered orally), which leads to a decrease in systemic exposure of the active metabolite clopidogrel by an average of 40% and a decrease in the maximum suppression of (ADP-induced) platelet aggregation by an average of 14%.
When clopidogrel was used simultaneously with a fixed combination of 20 mg esomeprazole/81 mg acetylsalicylic acid (ASA), compared with the use of clopidogrel alone, in a study involving healthy volunteers, a decrease in systemic exposure to the active metabolite of clopidogrel was observed by almost 40%. However, the maximum levels of inhibition of (ADP-induced) platelet aggregation in these healthy volunteers were similar in the clopidogrel and clopidogrel fixed combination (esomeprazole/ASA) groups.
Both observational and clinical studies have provided conflicting data regarding the clinical consequences of the pharmacokinetic/pharmacodynamic interaction of esomeprazole on major cardiovascular events. As a precaution, concomitant use of clopidogrel should be avoided.
When used simultaneously with tacrolimus
increased serum concentrations
of tacrolimus are possible.
Effect of drugs on the pharmacokinetics of esomeprazole
The isoenzymes 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 CYP3A4 isoenzyme), the AUC value of esomeprazole increases by 2 times.
Concomitant use of esomeprazole and a 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 long-term therapy is necessary, the issue of reducing the dose of esomeprazole should be considered.
Drugs that induce CYP2C19 and CYP3A4 isoenzymes, such as rifampicin and St. John's wort preparations, when used simultaneously with esomeprazole, may lead to a decrease in the concentration of esomeprazole in the blood plasma by accelerating the metabolism of esomeprazole.
Instructions for use of EMANERA®
Studies were conducted only in adults.
Effect of esomeprazole on the pharmacokinetics of other active substances
Medicines whose absorption depends on pH value
Suppression of hydrochloric acid secretion during treatment with esomeprazole and other PPIs may lead to a change (decrease or increase) in the absorption of drugs, the absorption of which depends on the pH of the gastric juice. As with other drugs that reduce gastric acidity, while taking esomeprazole, the absorption of drugs such as ketoconazole, itraconazole and erlotinib may decrease, and digoxin may increase. The simultaneous use of omeprazole (20 mg/day) and digoxin in healthy volunteers led to an increase in the bioavailability of the latter by 10% (up to 30% in 2 out of 10 subjects). Digoxin toxicity has been reported rarely. However, caution should be exercised when prescribing esomeprazole in high doses to elderly patients. When used, therapeutic drug monitoring of digoxin should be increased.
Omeprazole has been observed to interact with some protease inhibitors. The clinical significance and mechanisms of interaction are not fully understood. An increase in gastric pH during treatment with omeprazole may affect the absorption of protease inhibitors. Other possible mechanisms of interaction are through inhibition of CYP2C19. When taken concomitantly with omeprazole, a decrease in serum concentrations of atazanavir and nelfinavir was observed, so the simultaneous administration of these drugs is not recommended. Co-administration of omeprazole (40 mg 1 time/day) with atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a significant decrease in the bioavailability of atazanavir (by approximately 75% AUC, Cmax and Cmin). Increasing the dose of atazanavir to 400 mg did not compensate for this effect. Co-administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg to healthy volunteers resulted in a decrease in atazanavir AUC by approximately 30% compared to the values observed with atazanavir 300 mg/ritonavir 100 mg once daily without omeprazole. Concomitant use of omeprazole (40 mg 1 time/day) reduced the average AUC, Cmax and Cmin values of nelfinavir by 36-39%, and the average AUC, Cmax and Cmin values of its pharmacologically active metabolite M8 by 75-92%. When co-administered with omeprazole (40 mg 1 time / day), an increase in the serum concentration of saquinavir (together with ritonavir) was observed (80-100%). Concomitant use of omeprazole at a dose of 20 mg 1 time/day had no effect on the AUC of darunavir (together with ritonavir) and amprenavir (together with ritonavir). Co-administration of esomeprazole at a dose of 20 mg 1 time/day had no effect on the AUC of amprenavir (either when taken concomitantly with or without ritonavir). The use of omeprazole at a dose of 40 mg 1 time / day had no effect on the AUC of lopinavir (together with ritonavir). Due to the similar pharmacodynamic action and similar pharmacokinetic properties of omeprazole and esomeprazole, co-administration of esomeprazole and atazanavir is not recommended, and co-administration of esomeprazole and nelfinavir is contraindicated.
Active substances metabolized by CYP2C19
Esomeprazole inhibits CYP2C19, the main enzyme involved in its metabolism. Thus, when esomeprazole is combined with active substances metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., the plasma concentrations of these active substances may increase, which may require dose reduction. This should be especially taken into account when prescribing esomeprazole for on-demand therapy. Concomitant use of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, was accompanied by a 45% decrease in clearance of the latter. Administration of esomeprazole 40 mg to patients with epilepsy resulted in a 13% increase in plasma phenytoin concentrations at the end of the dose. In this regard, when prescribing or discontinuing esomeprazole during phenytoin therapy, it is recommended to monitor plasma concentrations of phenytoin. Omeprazole (40 mg 1 time/day) increased the Cmax and AUCt of voriconazole (CYP2C19 substrate) by 15% and 41%, respectively.
When esomeprazole 40 mg was administered (in a clinical study) to patients taking warfarin, coagulation time remained within acceptable limits. However, during the post-marketing period, several isolated clinically significant cases of increased INR have been observed during concomitant use of these drugs. When initiating or discontinuing therapy with esomeprazole during treatment with warfarin or other coumarin derivatives, monitoring is recommended.
Omeprazole, like esomeprazole, acts as an inhibitor of CYP2C19. In a crossover study, omeprazole administered to healthy volunteers at a dose of 40 mg increased the Cmax and AUC of cilostazol by 18% and 26%, respectively, and one of its active metabolites by 29% and 69%, respectively.
Concomitant administration of esomeprazole 40 mg resulted in an increase in the following parameters of cisapride in healthy volunteers:
- AUC - by 32%, T1/2 - by 31%, without a significant change in Cmax of cisapride in plasma. The slight increase in the QTc interval with cisapride alone was not exacerbated by the addition of esomeprazole.
Esomeprazole does not have a clinically significant effect on the pharmacokinetics of amoxicillin and quinidine.
Short-term studies evaluating the co-administration of esomeprazole and naproxen or rofecoxib did not reveal a clinically significant pharmacokinetic interaction.
Results from studies in healthy volunteers demonstrated a pharmacokinetic/pharmacodynamic interaction between clopidogrel (loading dose 300 mg/maintenance dose 75 mg) and esomeprazole (40 mg/day, orally), resulting in an average reduction in exposure (AUC) of the active metabolite of clopidogrel 40% and a decrease in the maximum inhibition (ADP-induced) platelet aggregation by an average of 14%.
When clopidogrel was used together with the fixed combination of esomeprazole 20 mg + acetylsalicylic acid 81 mg, the exposure (AUC value) of the active metabolite of clopidogrel was reduced by almost 40% compared with clopidogrel monotherapy. At the same time, the maximum levels of inhibition of (ADP-induced) platelet aggregation were the same in both groups.
Data on the clinical manifestations of the pharmacokinetic/pharmacodynamic interaction of esomeprazole in terms of major cardiovascular events obtained from experimental and clinical studies are conflicting. As a precaution, the combined use of these drugs should be avoided.
Unknown mechanism
With the simultaneous administration of esomeprazole and tacrolimus, an increase in the concentration of the latter in plasma was recorded.
Some patients have experienced an increase in methotrexate levels when taken together with a PPI. When prescribing high doses of methotrexate, the need for temporary withdrawal of esomeprazole should be assessed.
Effect of other active substances on the pharmacokinetics of esomeprazole
Esomeprazole is metabolized by CYP2C19 and CYP3A4. The combined use of esomeprazole and the CYP3A4 inhibitor clarithromycin (500 mg 2 times / day) led to a twofold increase in the AUC value of esomeprazole. Concomitant use of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4 may result in a more than twofold increase in the AUC value of esomeprazole. The CYP2C19 and CYP3A4 inhibitor voriconazole increased the AUCt of omeprazole by 280%. Usually in such situations no dose adjustment of esomeprazole is required. However, the need for dose adjustment should be assessed in patients with severely impaired liver function, as well as during long-term therapy.
The use of drugs that induce CYP2C19 or CYP3A4 (rifampicin and St. John's wort) may lead to decreased plasma concentrations of esomeprazole.
