Composition
active ingredient: esomeprazole;
1 tablet contains esomeprazole magnesium (amorphous), equivalent to esomeprazole 20 mg or 40 mg
excipients: spherical sugar, hydroxypropyl cellulose, crospovidone, povidone, macrogol 400, talc, hypromellose phthalate, diethyl phthalate, macrogol 6000, microcrystalline cellulose, sodium stearyl fumarate, macrogol 4000, Opadry 0ZV86651 brown (hydroxypropyl methylcellulose, titanium dioxide (E171), macrogol 4000, talc, iron oxide red (E172)).
Dosage form
The tablets are enteric-coated.
Pharmacological group
Drugs for the treatment of peptic ulcer disease and GERD. Proton pump inhibitors.
PBX code A02B C05.
Indication
Gastroesophageal reflux disease:
treatment of erosive reflux esophagitis; for long-term treatment to prevent relapse; symptomatic treatment of GERD.
In combination with antibacterial agents for the eradication of Helicobacter pylori:
Treatment of duodenal ulcers associated with Helicobacter pylori; prevention of recurrence of peptic ulcers in patients with ulcers caused by Helicobacter pylori.
Treatment and prevention of ulcers caused by long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs):
treatment of ulcers caused by NSAID therapy; prevention of gastric and duodenal ulcers in patients at risk due to NSAID use.
Long-term treatment after intravenous prophylaxis of rebleeding from peptic ulcers.
Treatment of Zollinger-Ellison syndrome.
Contraindication
Hypersensitivity to esomeprazole, substituted benzimidazoles or other components of the drug.
Pemozar, like other proton pump inhibitors, should not be used with atazanavir, nelfinavir.
Method of administration and doses
Pemozar tablets should be swallowed whole with sufficient liquid. The tablets should not be chewed or crushed.
Patients who have difficulty swallowing may be advised to dissolve the tablet in
100 ml of still water. No other liquids should be used as they may damage the intestinal lining. The water in the glass should be shaken to dissolve the tablet. Drink the liquid with the microgranules immediately or within 30 minutes. You should take another half glass of water, rinse the walls with water and drink. The microgranules should not be chewed or crushed.
For patients who have difficulty swallowing, the tablet can be administered via a nasogastric tube, after dissolving it in half a glass of still water. It is very important that the syringe and tube are compatible for this procedure.
Administration of the drug through a nasogastric tube:
1. Place the tablet in a suitable syringe and fill it with approximately 25 ml of water and 5 ml of air. Some tubes may require 50 ml of water to prevent the tablet from becoming difficult to pass through the tube.
2. Shake the syringe for 2 minutes to disintegrate the tablet.
3. Hold the syringe vertically, tip up, and check the patency of the tip.
4. Attach the syringe to the probe, holding it vertically.
5. Shake the syringe and turn it upside down. Quickly inject 5-10 ml of liquid. Invert the syringe after injection and shake again (the syringe should be held vertically to avoid clogging the tip).
6. Invert the syringe again and inject another 5-10 ml of fluid into the tube. Repeat the procedure until the syringe is empty.
7. To flush out any remaining medication, fill the syringe with 25 ml of water and 5 ml of air, shake the syringe, invert it, and quickly inject the fluid. Some probes may require 50 ml of water.
Adults and children over 12 years old
Gastroesophageal reflux disease
Treatment of erosive reflux esophagitis: 40 mg once daily for 4 weeks. An additional 4 weeks are recommended for patients whose esophagitis has not been cured or whose symptoms persist.
Long-term treatment of relapses in patients with cured esophagitis: 20 mg once daily.
Symptomatic treatment of GERD: 20 mg once daily in patients without esophagitis. If symptom control is not achieved within 4 weeks of treatment, the patient should be evaluated. If symptoms resolve, 20 mg once daily may be sufficient for continued control. For adults, the following regimen may be used:
"As needed" by taking 20 mg once daily. In patients who have received NSAIDs and are at risk of developing gastric or duodenal ulcers, further control of symptoms using the "as needed" regimen is not recommended.
adults
In combination with antibacterial agents for eradication of Helicobacter pylori
Treatment of duodenal ulcer associated with Helicobacter pylori: 20 mg of Pemozar with 1 g of amoxicillin and 500 mg of clarithromycin 2 times a day for 7 days.
Prevention of recurrence of peptic ulcers in patients with ulcers caused by Helicobacter pylori: 20 mg of Pemozar with 1 g of amoxicillin and 500 mg of clarithromycin 2 times a day for 7 days.
Treatment and prevention of ulcers caused by long-term use of NSAIDs
Treatment of gastric ulcers caused by NSAID therapy: the recommended dose is 20 mg once daily. The duration of treatment is 4-8 weeks.
Prevention of gastric and duodenal ulcers associated with NSAID treatment in patients at risk: the recommended dose is 20 mg once daily.
40 mg once daily for 4 weeks. The period of oral administration of Pemozard is preceded by therapy aimed at suppressing acidity, which consists in the use of Pemozard, a solution for infusion.
Treatment of Zollinger-Ellison syndrome: 40 mg 2 times a day. The dosage should be selected individually, the duration of treatment is determined by clinical indications. According to the obtained clinical data, in most patients the disease can be controlled by taking between 80 and 160 mg of esomeprazole per day. If the dose exceeds 80 mg/day, it should be divided into two doses.
Kidney dysfunction
No dose adjustment is required for patients with renal impairment. Due to the lack of experience in the use of Pemozar in patients with severe renal insufficiency, the drug should be administered with caution to such patients (see Section "Pharmacological properties").
Liver dysfunction
No dose adjustment is required for patients with mild to moderate hepatic impairment. For patients with severe hepatic impairment, the maximum dose of Pemozide should not exceed 20 mg (see section 5.1).
Elderly patients
Dose adjustment is not required for elderly patients.
Children under 12 years old
Pemozar should not be used in children under 12 years of age, as there is no data on such use.
Adverse reactions
The following adverse reactions have been reported during clinical trials and after the introduction of esomeprazole into widespread medical practice. No dose-related effect was observed. Adverse reactions are classified according to frequency: common (> 1/100, <1/10); uncommon (> 1/1,000, <1/100); rare (> 1/10,000, <1/1,000) and very rare (<1/10,000).
Disorders of the hematopoietic system
Rarely, leukopenia, thrombocytopenia.
Very rarely agranulocytosis, pancytopenia.
On the part of the immune system
Rarely, hypersensitivity reactions such as fever, angioedema and anaphylactic reaction/shock.
metabolic disorder
Uncommon peripheral edema.
Rarely, hyponatremia.
Very Rare: hypomagnesemia; severe hypomagnesemia may lead to hypoglycemia.
mental disorders
Uncommon: insomnia.
Rare: agitation, depression, confusion.
Very rarely, aggression, hallucinations.
From the nervous system
Frequent headaches.
Uncommon: weakness, paresthesia, drowsiness.
Rare: taste disturbance.
visual impairment
Rarely, blurred vision.
From the organ of hearing
Uncommon: dizziness.
Respiratory system disorders
Rarely, bronchospasm.
indigestion
Often abdominal pain, constipation, diarrhea, bloating, nausea, vomiting.
Uncommon: dry mouth.
Rarely, stomatitis, candidiasis of the gastrointestinal tract.
Very rare is microscopic colitis.
Digestive system disorders
Uncommon: increased liver enzymes.
Rarely, hepatitis with or without jaundice.
Very rarely, liver failure, encephalopathy in patients with liver disease.
Skin and soft tissue
Uncommon: dermatitis, itching, urticaria, rash.
Rarely alopecia, photosensitivity.
Very rarely erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Musculoskeletal disorders
Rare: arthralgia, myalgia.
Very rarely muscle weakness.
Renal and urinary disorders
Very rarely, interstitial nephritis.
Reproductive system disorders:
Very rare: gynecomastia.
general disorders
Rare: weakness, increased sweating.
Overdose
Data on overdose are limited. Gastrointestinal symptoms and weakness have been described after taking 280 mg of esomeprazole. A single dose of 80 mg of esomeprazole is unlikely to cause serious adverse effects. No specific antidote is known.
Esomeprazole is highly bound to plasma proteins and is therefore not dialysable. Treatment is symptomatic.
Use during pregnancy and breastfeeding
Clinical data on the use of Pemozar in pregnant women are limited. Animal studies do not indicate direct or indirect harmful effects on embryonal/fetal development. Caution should be exercised when prescribing the drug to pregnant women.
It is not known whether esomeprazole is excreted in breast milk. No studies have been conducted on the use of esomeprazole during breastfeeding, therefore Pemozar should not be used during breastfeeding.
Children.
Pemozar should not be used in children under 12 years of age, as there is no data on such use.
Application features
In the presence of alarming symptoms (e.g. marked weight loss, nausea, dysphagia, hematemesis or melaena) and in cases where gastric ulcer is suspected or present, malignancy should be excluded, as the use of Pemozar may alter symptoms and delay the determination of the correct diagnosis.
Patients taking the drug for a long time (especially those taking it for more than a year) should be under regular supervision.
When prescribing esomeprazole for the eradication of Helicobacter pylori, it is necessary to consider the possible drug interactions of all components of the triple therapy. Clarithromycin is a potent CYP3A4 inhibitor, and its contraindications and interactions should be considered (if triple therapy is used in patients taking other drugs that are metabolized by CYP3A4, such as cisapride, concomitantly with esomeprazole).
This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicinal product.
The use of proton pump inhibitors may slightly increase the risk of gastrointestinal infections such as Salmonella and Campylobacter.
Concomitant use of esomeprazole and atazanavir is not recommended. If the combination of atazanavir with proton pump inhibitors cannot be avoided, it is recommended to closely monitor patients in a hospital setting and increase the dose of atazanavir to 400 mg with 100 mg ritonavir; the dose of esomeprazole should not exceed 20 mg.
In healthy subjects, a pharmacokinetic/pharmacodynamic interaction was observed between clopidogrel (loading dose 300 mg/daily maintenance dose 75 mg) and esomeprazole (40 mg/day orally), resulting in an average 40% decrease in exposure to the active metabolite of clopidogrel and an average 14% decrease in maximal inhibitory activity (ADP-induced) on platelet aggregation. Accordingly, the use of esomeprazole and clopidogrel alone should be avoided.
The ability to influence the reaction speed when driving or working with other mechanisms.
Treatment with Pemozar does not affect the ability to drive or operate machinery. In cases where dizziness and blurred vision occur during treatment, you should refrain from driving or operating machinery.
Interaction with other drugs and other types of interactions.
Effect of esomeprazole on the pharmacokinetics of other drugs. Reduced gastric acidity during the use of esomeprazole may increase or decrease the absorption of drugs if their absorption depends on gastric acidity.
As with other drugs that reduce gastric acidity, the absorption of drugs such as ketoconazole, itraconazole and erlotinib may be reduced, while the absorption of drugs such as digoxin may be increased by treatment with esomeprazole and acetylsalicylic acid. Concomitant use of omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (in two out of ten subjects by 30%).
Omeprazole has been reported to interact with some protease inhibitors. The clinical significance and mechanisms of such interactions are unknown. Increased gastric pH during treatment with the drug may alter the absorption of protease inhibitors. Another possible mechanism of interaction is inhibition of CYP 2C19. Atazanavir and nelfinavir serum levels have been reported to decrease when co-administered with omeprazole, and their concomitant use is therefore not recommended. Despite the similarity of pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, the concomitant use of esomeprazole with atazanavir is not recommended. The concomitant use of esomeprazole with nelfinavir is contraindicated.
Esomeprazole inhibits 2C19, the main enzyme that metabolizes esomeprazole. Therefore, when esomeprazole is used in combination with drugs that are metabolized by 2C19 (such as diazepam, citalopram, imipramine, clomipramine, phenytoin), the plasma concentrations of these drugs may be increased, so a dose reduction may be necessary. This should be taken into account, especially when prescribing esomeprazole "if needed". The simultaneous use of 30 mg esomeprazole leads to a 45% decrease in the clearance of the CYP2C19 substrate diazepam. The simultaneous use of 40 mg esomeprazole leads to a 13% increase in the plasma level of phenytoin in patients with epilepsy. It is recommended to monitor the plasma concentration of phenytoin when prescribing or discontinuing therapy with esomeprazole. In clinical studies, the use of 40 mg esomeprazole in patients taking warfarin showed that coagulation times were within normal limits. Post-marketing experience with oral esomeprazole indicates a few isolated cases of clinically significant increases in international normalized ratio (INR) during concomitant use of esomeprazole and warfarin. It is recommended to monitor INR at the beginning and after the end of concomitant treatment with esomeprazole and warfarin or other coumarin derivatives.
In healthy volunteers, concomitant administration of 40 mg esomeprazole with cisapride resulted in a 32% increase in area under the concentration-time curve (AUC) and a 31% increase in elimination half-life (t1/2), but no significant increase in peak plasma levels of cisapride. A moderately prolonged QT interval was observed after administration of cisapride alone, which was not further prolonged when cisapride was administered in combination with esomeprazole.
Increased serum levels of tacrolimus have been reported with concomitant use of esomeprazole.
Increased blood levels of methotrexate have been reported in some patients when co-administered with proton pump inhibitors. If high doses of methotrexate are required, temporary withdrawal of esomeprazole should be considered.
Omeprazole has been reported to interact with some antiretroviral agents. The clinical significance and mechanism of this interaction are not always known. The increase in gastric pH during the use of these drugs may alter the absorption of antiretroviral agents. Other mechanisms of interaction may be related to the CYP 2C19 enzyme. In the case of some antiretroviral agents, such as atazanavir and nelfinavir, decreased serum levels of the latter have been observed when used concomitantly with the drug. Therefore, concomitant use of omeprazole and drugs such as atazanavir and nelfinavir is not recommended. Increased serum levels of other antiretroviral agents, such as saquinavir, have been reported. There are also other antiretroviral agents whose serum levels have remained unchanged when used concomitantly with omeprazole. Due to the similar pharmacodynamic effects and pharmacokinetic properties of omeprazole and esomeprazole, the concomitant use of esomeprazole and antiretroviral agents such as atazanavir and nelfinavir is not recommended.
The use of omeprazole (40 mg once daily) with atazanavir 300 mg and ritonavir 100 mg in healthy volunteers resulted in a significant decrease in the exposure of atazanavir (approximately
75% decrease in AUC, C max, C min). Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on the efficacy of atazanavir. Proton pump inhibitors, including esomeprazole, should not be used with atazanavir.
Esomeprazole did not show any clinically significant effect on the pharmacokinetics of amoxicillin or quinidine. No clinically significant pharmacokinetic interactions were observed with short-term concomitant use of esomeprazole and naproxen or rofecoxib.
Effects of other medicinal products on the pharmacokinetics of esomeprazole. Esomeprazole is metabolised by CYP2C19 and CYP3A4. Concomitant administration of esomeprazole and the CYP3A4 inhibitor clarithromycin (500 mg twice daily) resulted in a two-fold increase in esomeprazole exposure. Concomitant administration of esomeprazole and a combined CYP2C19 and CYP3A4 inhibitor such as voriconazole may result in a more than two-fold increase in esomeprazole exposure.
The CYP2C19 and CYP3A4 inhibitor voriconazole increased the AUCτ of omeprazole by 280%.
Dose adjustment of esomeprazole should be considered in patients with severe hepatic impairment and in case of long-term treatment.
The results of studies in healthy subjects demonstrated the presence of a pharmacokinetic/pharmacodynamic interaction between clopidogrel (loading dose 300 mg/daily maintenance dose 75 mg) and esomeprazole (40 mg/day orally), which resulted in a decrease in exposure to the active metabolite of clopidogrel by an average of 40% and a decrease in maximal inhibition of (ADP-induced) platelet aggregation by an average of 14%.
However, it remains unclear to what extent this interaction may be of clinical relevance. Based on the results of one prospective randomized (but not completed) trial (involving more than 3760 people; comparing placebo and omeprazole 20 mg treatment in patients treated with clopidogrel and acetylsalicylic acid) and non-randomized post-hoc analyses of data from large prospective randomized clinical outcome trials (more than 4700 patients), there is no evidence of an increased risk of adverse cardiovascular outcomes with the concomitant use of clopidogrel and PPIs, including esomeprazole.
A number of observational studies have shown conflicting results regarding whether the risk of CV thromboembolic events is increased if a patient receives clopidogrel together with a PPI.
In a study in healthy subjects, in which clopidogrel was co-administered with a combination of 20 mg esomeprazole and 81 mg acetylsalicylic acid compared with clopidogrel alone, a decrease in exposure to the active metabolite of clopidogrel of almost 40% was observed. However, the maximum inhibitory activity (ATP-induced) on platelet aggregation in these subjects was the same in the groups taking clopidogrel alone and clopidogrel + combination (esomeprazole + acetylsalicylic acid), which is probably explained by the simultaneous administration of a lower dose of acetylsalicylic acid.
Drugs that induce CYP2C19, CYP3A4, or both enzymes (such as rifampicin or St. John's wort) may lead to decreased serum levels of esomeprazole by accelerating its metabolism.
Pharmacological properties
Esomeprazole is the S-isomer of omeprazole, which reduces gastric acid secretion by a specifically targeted mechanism of action. It is a specific inhibitor of the proton pump in the parietal cell. The R- and S-isomers of omeprazole have the same pharmacodynamic activity.
Esomeprazole is a weak base, it concentrates and converts to the active form in the highly acidic environment of the secretory tubules of the parietal cell, where it inhibits the enzyme H + K + -ATPase - the acid pump, and also inhibits basal and stimulated acid secretion.
Effect on gastric juice secretion
After administration of 20 mg and 40 mg esomeprazole, the onset of action is within one hour. After repeated administration of 20 mg esomeprazole once daily for 5 days, the mean peak acid output after pentagastrin stimulation is reduced by 90% when measured 6-7 hours after the dose on day 5.
After 5 days of oral administration of esomeprazole 20 mg and 40 mg, gastric pH was greater than 4 for a mean of 13 and 17 hours, respectively, and for more than 24 hours in patients with symptomatic reflux esophagitis. The proportion of patients who had gastric pH greater than 4 for 8, 12, and 16 hours, respectively, after 20 mg esomeprazole was
76%, 54% and 24%. The corresponding proportions for esomeprazole 40 mg were 97%, 92% and 56%.
When using AUC as an indirect indicator of plasma concentration, the dependence of acid secretion suppression on drug exposure was shown.
Therapeutic effects of acid suppression
Treatment of reflux esophagitis with esomeprazole 40 mg was successful in approximately 70% of patients after 4 weeks of treatment and in 93% after 8 weeks of treatment.
Esomeprazole 20 mg twice daily for one week, together with appropriate antibiotics, resulted in successful eradication of Helicobacter pylori in approximately 90% of patients. After one week of treatment, no further antisecretory monotherapy was required for successful ulcer healing and symptom relief in uncomplicated duodenal ulcers.
Other effects related to inhibition of acid secretion
During the period of use of antisecretory drugs, the concentration of gastrin in the blood plasma increases in response to a decrease in acid secretion.
The increase in the number of ECL cells may be related to the increase in plasma gastrin levels observed in some patients with long-term use of esomeprazole.
There have been several reports of an increased incidence of gastric granular cysts with long-term use of antisecretory drugs. These phenomena are a physiological consequence of prolonged inhibition of acid secretion and are benign and reversible.
The reduction in gastric acid secretion caused by any proton pump inhibitor increases the number of bacteria normally present in the stomach. Treatment with proton pump inhibitors may increase the risk of gastrointestinal infections caused by, for example, Salmonella or Campylobacter.
Pemozar was more effective than ranitidine in treating stomach ulcers in patients treated with NSAIDs (nonsteroidal anti-inflammatory drugs), including selective COX-2 inhibitors.
Pemozar was effective in preventing gastric and duodenal ulcers in patients treated with NSAIDs (in patients over 60 years of age and/or with a history of ulcer), including COX-2 selective NSAIDs.
Pharmacokinetics.
Esomeprazole is acid-labile and is administered orally in the form of enteric-coated granules. Conversion to the R-isomer in vivo is negligible. Absorption of esomeprazole is rapid, with peak plasma concentrations achieved within 1 h.
1-2 hours after administration. Bioavailability is 64% after a single dose of 40 mg and increases to 89% after repeated administration once daily. 20 mg of esomeprazole corresponds to values of 50% and 68%. The volume of distribution in healthy volunteers at steady state is 0.22 l/kg body weight. Esomeprazole is 97% bound to plasma proteins.
Food intake slows down and reduces the absorption of esomeprazole, but does not affect the effect of esomeprazole on gastric acidity.
Metabolism and excretion
Esomeprazole is completely metabolised by the cytochrome P450 (CYP) system. The main part of the metabolism of esomeprazole depends on the polymorphic 2C19, which is responsible for the formation of the hydroxy- and desmethyl metabolites of esomeprazole. The other part depends on a second specific isoform, CYP3A4, which is responsible for the formation of esomeprazole sulfone, the main metabolite in the blood plasma.
The parameters listed below mainly reflect pharmacokinetics in individuals with functional 2C19 enzyme (extensive metabolizers).
Total plasma clearance is about 17 l/h after a single dose and about
1.3 hours after repeated once daily dosing. The pharmacokinetics of esomeprazole have been studied at doses up to 40 mg twice daily. The area under the plasma concentration-time curve increases with repeated dosing of esomeprazole. This increase is dose-dependent and results in a more dose-proportional increase in AUC after repeated dosing. This time- and dose-dependence is explained by a decrease in first-pass metabolism and systemic clearance associated with inhibition of the 2C19 enzyme by esomeprazole and/or its sulfmetabolite. Esomeprazole is completely eliminated from plasma between doses with no tendency for accumulation when the drug is taken once daily.
The main metabolites of esomeprazole do not affect gastric secretion. About 80% of an oral dose of esomeprazole is excreted as metabolites, the rest in the feces. Less than 1% of the parent drug is found in the urine.
Special patient groups
Approximately 2.9 ± 1.5% of the patient population is deficient in the 2C19 enzyme (referred to as poor metabolisers). In these individuals, esomeprazole is metabolised predominantly by CYP3A4. After repeated once-daily dosing with 40 mg esomeprazole, the mean area under the plasma concentration-time curve in poor metabolisers is approximately 100% higher than in subjects with normal 2C19 enzyme function (extensive metabolisers). The maximum plasma concentration is increased by approximately 60%. These findings have no impact on the dosage of esomeprazole.
The metabolism of esomeprazole is not significantly altered in elderly patients (71 to 80 years).
After a single dose of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was 30% higher in women than in men. No gender-related differences were observed with repeated once-daily dosing. These findings do not impact the dosing of esomeprazole.
Patients with hepatic/renal impairment
The metabolism of esomeprazole in patients with mild to moderate hepatic dysfunction may be impaired. The rate of metabolism is reduced in patients with severe hepatic impairment, resulting in a 2-fold increase in the area under the plasma concentration-time curve. Thus, the maximum dose for patients with severe hepatic impairment is 20 mg. Esomeprazole and its metabolites do not tend to accumulate when administered once daily.
Studies in patients with renal impairment have not been conducted. Since the kidneys are responsible for the excretion of esomeprazole metabolites and not the parent compound, no changes in metabolism are expected in patients with renal impairment.
Use in pediatrics
Children 12-18 years: After multiple administration of 20 mg and 40 mg esomeprazole, the overall exposure and time to peak plasma concentration were similar to those in adults.
Main physicochemical properties
20 mg are red-brown, oval, biconvex, film-coated tablets debossed with “E5” on one side and plain on the other side.
40 mg are red-brown, oval, biconvex, film-coated tablets debossed with “E6” on one side and plain on the other side.
Expiration date
2 years.
Storage conditions
Store at a temperature not exceeding 30 °C in the original packaging.
Keep out of reach of children.
Packaging
No. 14 (7 × 2) - 7 tablets in a blister, 2 blisters in a cardboard box.
No. 30 - 30 tablets in a plastic bottle, 1 bottle in a cardboard box.
Vacation category
According to the recipe.
