International non-proprietary name:Esomeprazole

Composition
Composition
Active substance: 1 tablet contains 40 mg of esomeprazole (in the form of esomeprazole magnesium trihydrate)
there is
Excipients: calcium carbonate, magnesium oxide, crospovidone, povidone, refined talc,
HPMC E5, magnesium stearate, ethyl cellulose N20, titanium dioxide, instacoat EN-HPMCP-
IC-EN-815 BROWN IH.

Description
Brown, round, biconvex, enteric-coated tablets.

Pharmacotherapeutic group
Proton pump inhibitor.
ATC code:A02BC05.

pharmacological properties
Pharmacodynamics
Esomeprazole is the S-isomer of omeprazole; by specifically inhibiting the proton pump in the parietal cells, it reduces the secretion of hydrochloric acid in the stomach. S- and R-isomers of omeprazole have similar pharmacodynamic activity. 
Mechanism of action
Esomeprazole is a weak alkaline substance; in the highly acidic environment of the stomach, it accumulates in the secretory tubules of the parietal cells and changes to an active form, inhibiting the proton pump (H+K+ATF-ase enzyme). Esomeprazole reduces both basal and stimulated secretion of hydrochloric acid.
Pharmacodynamic effects 
After oral administration of esomeprazole 20 mg and 40 mg, the effect begins within 1 hour. 
After repeated administration at a dose of 20 mg once a day for 5 days, after stimulation with pentagastrin, the average maximum concentration of hydrochloric acid decreases by 90% (when measuring the concentration of acid 6-7 hours after administration on the 5th day of treatment). 
After 5 days of oral administration of esomeprazole 20 mg and 40 mg in patients with clinical symptoms of gastroesophageal reflux, intragastric pH was maintained above 4 for an average of 13 and 17 hours of 24 hours, respectively. Against the background of taking esomeprazole 20 mg per day, intragastric pH above 4 was maintained in 76%, 54% and 24% of patients for no less than 8, 12 and 16 hours, respectively. For esomeprazole 40 mg, this rate is 97%, 92%, and 56%, respectively. 
The correlation between the concentration of the drug in plasma and the inhibition of acid secretion was determined (the AUC parameter is used to estimate the concentration ("area under the "concentration-time" curve). 
When esomeprazole is taken at a dose of 40 mg, recovery of reflux esophagitis occurs in 78% of patients after 4 weeks, and in 93% of patients after 8 weeks. 
Esomeprazole in combination with appropriate antibiotics leads to successful eradication of Helicobacter pylori in approximately 90% of patients when taken at a dose of 20 mg twice daily for 1 week.
In patients with uncomplicated duodenal ulcer, there is no need to continue monotherapy with antisecretory drugs for ulcer healing and symptom relief after a 1-week eradication treatment course.
In a randomized, double-blind, placebo-controlled clinical trial, patients with endoscopically confirmed peptic ulcer bleeding characterized as Forrest Ia, Ib, IIa, or IIb (9%, 43%, 38%, and 10%, respectively) administered esomeprazole solution for infusion. (n=375) or randomized   to placebo (n=389).
Pharmacokinetics
Absorption 
Esomeprazole is resistant to acidic environment, therefore tablets containing coated granules resistant to the effect of stomach acid are used for oral administration. 
Conversion to the R-isomer under in vivo conditions is negligible. Absorption of esomeprazole occurs quickly; the maximum concentration in the blood plasma (Cmax) is reached approximately 1-2 hours after taking the drug (Tmax). The absolute bioavailability of esomeprazole after a single dose of 40 mg is 64% and increases to 89% after repeated administration once a day. For 20 mg esomeprazole, this indicator is 50% and 68%, respectively. Food intake slows and reduces the absorption of esomeprazole, but this does not affect the effectiveness of the drug in inhibiting the secretion of hydrochloric acid. 
Distribution
The estimated volume of distribution in healthy volunteers of the same weight was 0.22 l/kg. Its combination with plasma proteins is 97%.
Biotransformation
Esomeprazole is completely metabolized by the cytochrome P450 system. The main part of the drug's metabolism depends on polymorphic CYP2C19, which is responsible for the formation of hydroxy- and desmethylesomeprazole metabolites. Metabolism of the remaining part occurs through CYP3A4, another specific isoform responsible for the formation of its main metabolite - esomeprazole sulfone.
Exclusion
The following parameters mainly reflect pharmacokinetics in individuals with a functional CYP2C19 enzyme and active metabolism. Total plasma clearance is approximately 17 l/h and 9 l/h after single and repeated doses, respectively. The elimination half-life of esomeprazole is approximately 1.3 hours after oral repeated dosing once daily. When taken once a day, esomeprazole is completely removed from the blood plasma during the interval between doses and does not accumulate.
The main metabolite of esomeprazole does not affect the secretion of hydrochloric acid in the stomach. After oral administration, approximately 80% of the injected dose is excreted in urine as metabolites, less than 1% is unchanged, and the rest is excreted in feces. 
Linear/non-linear
The pharmacokinetics of esomeprazole have been studied for doses up to 40 mg taken twice a day. The area under the "concentration-time" curve (AUC) increases during repeated administration of the drug (due to the decrease in metabolism during the "first pass" through the liver and the decrease in systemic clearance due to the inhibition of the CYP2C19 isoenzyme of esomeprazole and/or its sulfone metabolite, the dose and non-linear dependence between AUC). 
Pharmacokinetics in a special group of patients
Patients with weak (inactive) metabolism
About 2.9±1.5% of the population lacks the functional enzyme CYP2C19 (they are called poor metabolizers). Metabolism of esomeprazole in these people occurs mainly through the enzyme CYP3A4. The mean AUC of esomeprazole was 100% higher in patients with active metabolism by the CYP2C19 enzyme when using repeated doses of 40 mg daily. 
In patients with inactive metabolism, the average maximum concentration in plasma is approximately 60% higher. The indicated properties do not affect the dosage of esomeprazole. 
Gender diversity
After a single dose of 40 mg of esomeprazole, mean AUC values are 30% higher in women than in men. After repeated administration of the drug once a day, no changes in pharmacokinetics were noted between men and women. These properties do not affect the dosage of esomeprazole.
Patients with liver failure
Metabolism of esomeprazole may be impaired in patients with mild to moderate hepatic impairment. In severe liver failure, metabolism decreases, which is accompanied by a 2-fold increase in AUC. Therefore, the dose of the drug in such patients should not exceed 20 mg.
Patients with renal failure 
Esomeprazole metabolism is not expected to be altered in patients with renal impairment.
When taken once a day, esomeprazole is completely removed from the blood plasma during the interval between doses and does not accumulate.
Elderly patients
In elderly patients (71-80 years old), the metabolism of esomeprazole does not change significantly.
Pediatric patients 
In adolescents aged 12-18 
In this age group, the AUC  values and the time to reach the maximum concentration in blood plasma after repeated administration of 20 mg and 40 mg esomeprazole were similar to the AUC and Tmax values in adults receiving both doses.
Instructions for use
Temzo 40 mg enteric-coated tablets are prescribed to adults for the treatment of the following diseases:
•    Symptomatic treatment of gastroesophageal reflux disease (GERD)
•    Erosive reflux esophagitis treatment
•    Zollinger-Ellison syndrome
•    For prevention of rebleeding after infusion solution therapy in older patients with gastric or duodenal ulcers 
Children over 12 years of age are prescribed for the treatment of the following diseases:
•    Symptomatic treatment of gastroesophageal reflux disease (GERD)
•    Treatment of erosive reflux esophagitis. 

Contraindications
Hypersensitivity to the active substance - esomeprazole, substituted benzimidazoles or any of the other ingredients in the preparation
People who are allergic to other proton pump inhibitors (pantoprazole, lansoprazole, rabeprazole, omeprazole)
• As with other proton pump inhibitors, esomeprazole should not be used with atazanavir or nelfinavir (medicines used to treat HIV (AIDS). 

Special instructions and precautions
Temzo coated tablets should be used with caution in the following cases. 
If you experience any of the following during treatment: 
-    unexplained weight loss
- causing pain or indigestion
-    beginning of vomiting with blood or food 
-    faeces are black and have bleeding spots 
contact your doctor immediately.
In these cases, if gastric ulcer is suspected or present, malignancy should be ruled out, as treatment with esomeprazole may alleviate symptoms and thus delay diagnosis.
Long-term use
Patients undergoing long-term treatment (especially those treated for more than a year) should be kept under regular supervision of a doctor.
"As needed" mode
Patients treated with the "as needed" regimen should be warned to consult a doctor if symptoms change. 
Eradication of Helicobacter pylori
Drug interactions of all components of combined triple therapy should be considered when prescribing esomeprazole for H. pylori eradication. Clarithromycin is a strong inhibitor of the CYP3A4 enzyme, so clarithromycin contraindications and interactions should be taken into account during triple combination therapy in patients receiving concomitant drugs that are metabolized by the CYP3A4 isoenzyme, such as cisapride.
Gastrointestinal infections
Treatment with PPIs may slightly increase the risk of gastrointestinal infections such as Salmonella and Campylobacter.
Absorption of vitamin B12 
Esomeprazole, like other proton pump inhibitors, can reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- and achlorhydria. This factor should be taken into account during long-term therapy in patients with low reserves of vitamin B12 or in patients with risk factors for reduced absorption.
Hypomagnesemia (decreased levels of magnesium in the blood)
Severe hypomagnesemia was observed in patients treated with proton pump inhibitors for at least 3 months, and in most cases for 1 year.  Severe signs of hypomagnesemia, fatigue, tetany, alertness, convulsions, dizziness, and ventricular arrhythmias may begin asymptomatically and may be subtle. In many cases, symptoms of hypomagnesemia subsided with magnesium replacement therapy and discontinuation of PPIs. If the patient needs long-term treatment with digoxin or other drugs that cause hypomagnesemia (for example, diuretics) together with a PPI, it is necessary to check the level of magnesium at the beginning of treatment and regularly during treatment.
Risk of fractures
Proton pump inhibitors may increase the risk of fractures of the hip, wrist, and spine when used in large doses and for long periods (more than 1 year), especially in elderly patients and patients with other risk factors. Observational studies show that proton pump inhibitors can increase the risk of fractures by 10-40%. This increase in risk may be partly due to other risk factors. Patients at high risk of developing osteoporosis should receive treatment according to current clinical recommendations. It is necessary to ensure that enough vitamin D and calcium enter their bodies. 

Semi-acute skin red hives
Rarely, subacute cutaneous urticaria has been reported with the use of proton pump inhibitors.
Co-administration of esomeprazole with atazanavir is not recommended. When the physician deems it necessary to use atazanavir with proton pump inhibitors, careful clinical observation is recommended when the dose of atazanavir is increased to 400 mg and ritonavir to 100 mg; the dose of esomeprazole should not exceed 20 mg. 
Esomeprazole is an inhibitor of the CYP2C19 enzyme. The possibility of interactions with drugs metabolized by CYP2C19 should be considered after starting or ending treatment with esomeprazole. An interaction between clopidogrel and esomeprazole has been observed. The clinical significance of this interaction is unknown. As a precaution, esomeprazole and clopidogrel should not be used at the same time. 
When esomeprazole is prescribed for treatment with the "as-needed" regimen, it should be considered that interactions between other drugs may occur due to changes in plasma concentration. 
Effect on the results of laboratory analyses
Elevated levels of CgA (chromogranin A) may affect neuroendocrine tumor screening results. To prevent this, treatment with esomeprazole should be temporarily stopped at least 5 days before determining the CgA level. 

Interaction with other drugs
Effects of esomeprazole on the pharmacokinetics of other drugs
Protease inhibitors 
There is information on the interaction of omeprazole with some protease inhibitors. The mechanisms underlying these interactions and their clinical significance are often unknown. An increase in the pH of the gastric juice during treatment with omeprazole may alter the absorption of protease inhibitors. Other possible mechanisms of interaction are related to CYP2C19 inhibition. 
Concomitant administration of atazanavir and nelfinavir with omeprazole may decrease serum levels of these drugs; combined use is not recommended. The use of omeprazole (40 mg once daily) and 300 mg atazanavir/100 mg ritonavir in healthy volunteers significantly decreases the exposure level of atazanavir (approximately 75% based on AUC, Cmax and Cmin). Increasing atazanavir to 400 mg does not compensate for the effect of omeprazole on the effect level of atazanavir. Administration of omeprazole (20 mg/day) with 400 mg atazanavir/100 mg ritonavir in healthy volunteers reduced the exposure to atazanavir by 30% compared to administration of 300 mg atazanavir/100 mg ritonavir once daily without omeprazole 20 mg. Concomitant use of omeprazole (40 mg 1 time per day) decreased the average AUC, Cmax and Cmin of nelfinavir by 36-39%, and the average AUC, Cmax and Cmin of the pharmacologically active metabolite M8 by 75-92%. 
For saquinavir (when used with ritonavir), an increase in plasma levels (80-100%) was noted when it was used with omeprazole (40 mg once daily). 
Taking omeprazole 20 mg once a day does not affect the effect level of darunavir (with ritonavir) and amprenavir (with ritonavir). Taking esomeprazole at a dose of 20 mg once a day does not affect the level of action of amprenavir (monotherapy or in combination with ritonavir).
Taking omeprazole 40 mg once a day does not affect the level of action of lopinavir (with ritonavir). 
Methotrexate
During the combined use of methotrexate with PPI, an increase in the level of methotrexate was observed in some patients. 
Esomeprazole may need to be discontinued when using high doses of methotrexate.
Tacrolimus
It has been reported that the simultaneous administration of esomeprazole increases the serum level of tacrolimus. Enhanced monitoring of tacrolimus concentration, as well as monitoring of renal function (creatinine clearance) should be carried out and, if necessary, the tacrolimus dose should be adjusted.
Medicines whose absorption depends on pH
During treatment, the use of esomeprazole and other PPI drugs that reduce the acidity of the stomach can increase or decrease the absorption of drugs whose absorption depends on pH. As with other antacid drugs, the absorption of drugs such as ketoconazole, itraconazole, and erlotinib may decrease and the absorption of drugs such as digoxin may increase when using esomeprazole.
Concomitant use of omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of the latter up to 10% (up to 30% in 2 out of 10 subjects). Digoxin toxicity has been rarely reported. However, caution should be exercised when esomeprazole is prescribed in high doses to elderly patients. Therapeutic drug monitoring of digoxin should subsequently be intensified.
Drugs metabolized by CYP2C19
Esomeprazole inhibits the activity of CYP2C19 enzyme, which is the main metabolic agent. Thus, esomeprazole warfarin, phenytoin, citalopram, imipramine, clomipramine, diazepam, etc. When combined with medical drugs that are metabolized by the CYP2C19 enzyme, plasma concentrations of these drugs may increase and dosages may need to be reduced. 
Diazepam
When used together with 30 mg of esomeprazole, the clearance of the CYP2C19 substrate of diazepam decreases by 45%. 
Phenytoin
When phenytoin is used together with esomeprazole 40 mg in patients with epilepsy, the minimum concentration of phenytoin increases by 13%. In this regard, it is necessary to monitor the concentration of phenytoin in the plasma at the beginning of treatment with esomeprazole and during the discontinuation of its use.
Voriconazole
Taking omeprazole (40 mg 1 time per day) increases the Cmax and AUC of voriconazole by 15% and 41%, respectively (CYP2C19 substrate). 
Sitostazol
Omeprazole acts as a CYP2C19 inhibitor like esomeprazole. In crossover studies with the participation of healthy subjects, omeprazole at a dose of 40 mg increased the Cmax and AUC of ciloztazole by 18% and 26%, respectively, and that of the active metabolite by 29% and 69%, respectively.
Cisapride
In healthy volunteers, the use of 40 mg of esomeprazole together with cisapride leads to an increase in the pharmacokinetic parameters of cisapride: AUC by 32% and T1/2 by 31%, but the concentration of cisapride in plasma did not change significantly. A slight prolongation of the QTc interval was observed after the use of cisapride alone, but no prolongation was observed with the subsequent use of cisapride in combination with esomeprazole.
Warfarin
In clinical studies, administration of 40 mg of esomeprazole in addition to warfarin patients was shown to not exceed the permissible limit of coagulation. However, observations in the post-registration period show that BNN increased clinically significantly during the combined use of both drugs. Therefore, monitoring should be carried out at the beginning and end of treatment with esomeprazole against the background of therapy with warfarin (or other coumarin derivatives).
Clopidogrel
Results of studies in healthy subjects have shown that the interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and esomeprazole (40 mg daily per os) resulted in an average 40% reduction in exposure to the active metabolite of clopidogrel and an increase in platelet aggregation (ADF-induced ) causes an average 14% decrease in maximal inhibition. In a study involving healthy volunteers, when clopidogrel was prescribed together with 20 mg esomeprazole + 81 mg acetylsalicylic acid in a fixed dose compared to the use of clopidogrel alone, a decrease in the effect of the active metabolite of clopidogrel was observed by about 40%. However, the maximum level of inhibition of platelet aggregation (stimulated by ADF) was the same in both groups. From the point of view of major cardiovascular events, the manifestation of the PK/FD interaction of esomeprazole has been noted in both observational and clinical studies.
As shown, esomeprazole did not significantly alter the pharmacokinetics of amoxicillin or quinidine.
Naproxen or rofecoxib
Short-term studies evaluating the use of esomeprazole in combination with naproxen and rofecoxib did not identify any clinically significant pharmacokinetic interactions.
Effects of other drugs on the pharmacokinetics of esomeprazole
CYP2C19 and CYP3A4 are involved in the metabolism of esomeprazole. The use of esomeprazole with CYP3A4 inhibitor clarithromycin (500 mg 2 times a day) led to a two-fold increase in the exposure (AUC) of esomeprazole. Co-administration of esomeprazole with inhibitors of both CYP2C19 and CYP3A4 isoforms may more than double the exposure of esomeprazole. 
Voriconazole, an inhibitor of CYP2C19 and CYP3A4, increased the AUCt of omeprazole by 280%. In such cases, there is no need to adjust the dose of esomeprazole, but in patients with severe liver dysfunction, the dose should be reviewed during long-term treatment.
Drugs that induce CYP2C19, CYP3A4, or one of them (such as rifampicin and St. John's wort) may decrease serum levels of esomeprazole by increasing its metabolism.

Use during pregnancy and lactation
Consult your doctor before taking any medication during pregnancy. 
Before you start using Tamzo coated tablets, tell your doctor if you are pregnant or planning to become pregnant. 
Pregnancy 
There is insufficient data on the use of esomeprazole in pregnant women.  
In epidemiological studies conducted with the use of a racemic mixture of omeprazole, during the observation of a large number of pregnant women, toxicity to the fetus and developmental defects were not detected. No direct or indirect adverse effects of esomeprazole on the embryo/fetus were found in animal studies. Pregnant women should be careful when prescribing the drug. If you discover that you are pregnant during your treatment, inform your doctor immediately.
Lactation period
The excretion of esomeprazole in breast milk is not known. There is insufficient information on the effects of esomeprazole in neonates/infants. Therefore, the drug should not be used during breastfeeding.
Reproductive period
Animal studies have revealed no direct or indirect adverse effects on reproductive function of the racemic mixture of oral omeprazole.

Effects on the ability to drive vehicles and other potentially dangerous mechanisms
Esomeprazole has little effect on the ability to drive vehicles and other potentially dangerous mechanisms. Rare side effects such as dizziness and blurred vision may occur during treatment with esomeprazole. When these reactions occur, patients are not recommended to use vehicles and other types of activities that require special attention and psychomotor reactions.

Method of use and dosage
Temzo coated tablets are taken with food or on an empty stomach. Tablets should be taken whole inside with a glass of water. Tablets should not be chewed or crushed. 
For patients who have difficulty swallowing, the tablet can be dissolved in half a glass of still water and drunk until completely dissolved. In this case, it will be easier to absorb. Do not use any other liquids as they may break down the enteric coating of the drug. Drink the solution immediately or within 30 minutes. Swallow the small granules that come out of the tablet without chewing. Do not allow the pellets to remain in the water for more than 30 minutes. After drinking, fill the glass halfway again with water, shake it and drink it too. For patients who cannot swallow, tablets can be dissolved in still water and administered through a gastric tube. It is important to carefully check the compatibility of the selected syringe and tube. 
The duration and dosage of Temzo 40 mg enteric-coated tablets depends on the course of the disease.
Gastroesophageal reflux disease
To adults
In the treatment of erosive reflux esophagitis, esomeprazole should be taken in a dose of 40 mg once a day. The duration of treatment is 4 weeks. 
In patients who do not recover after the first course of treatment or whose symptoms persist, an additional course of treatment is recommended within the next 4 weeks. 
To teenagers aged 12-18
For the treatment of inflammation and pain in the esophagus (erosive reflux esophagitis), it is recommended to take 40 mg once a day. Depending on the severity of the disease and your response to treatment, the total treatment period is 4-8 weeks. 
Prevention of rebleeding in gastric or duodenal ulcers 
After treatment with the infusion solution of proton pump inhibitors, it is taken in a dose of 40 mg once a day for 4 weeks.
Conditions that cause increased stomach acidity, including tumors that produce hormones that cause increased stomach acid secretion (Zollinger-Ellison syndrome)
The recommended starting dose of esomeprazole for adults is 40 mg 2 times a day. Then the choice of dose and duration of treatment is carried out individually depending on the course of the disease. Available clinical data show that many patients are treated with a daily dose of 80-160 mg of esomeprazole. A daily dose higher than 80 mg should be taken in two divided doses during the day.
Additional information on special groups of patients
Patients with renal failure
There is no need to adjust the dose in patients with impaired renal function. As there is limited experience of its use in patients with severe renal insufficiency, the drug should be prescribed with caution to such patients.
Patients with liver failure
No dose adjustment is required for patients with mild to moderate hepatic impairment. The maximum daily dose of esomeprazole in patients with severe liver failure should not exceed 20 mg.
Use in different age groups
Elderly patients
It can be used in the elderly. There is no need to adjust the dose. 
Pediatric patients 
Since there is no information on the use of the drug in children under 12 years of age, it is not recommended to prescribe it to this group of patients.
If you forget to take the drug
If you forget to take a Tamzo coated tablet, take the dose as soon as you remember and then resume regular use. 
If you forget to take the drug, do not take a double dose instead of the missed dose!
Do not stop taking the medicine without consulting your doctor!
Side effects
Like all medicines, Temzo coated tablets can have unwanted effects in patients who are sensitive to the substances contained in them.
Summary of the security profile
Side effects such as headache, abdominal pain, diarrhea, and nausea have been reported in clinical studies (as well as from postmarketing use).
Furthermore, the safety profile was similar across different dosage forms, indications, age groups and patient populations. 
The following adverse reactions have been identified or suspected during clinical trials of esomeprazole and during the postmarketing period. Dose-dependent side effects have not been identified. 
Observed additional reactions are classified according to organ systems and frequency of occurrence as follows: very often (≥1/10); often (≥1/100 to <1/10); sometimes (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10000); with an unknown frequency (the available data are insufficient to determine the frequency of occurrence).