Nexium powder 10 mg how to use. Terms of dispensing from pharmacies

One package contains:
active substance: esomeprazole magnesium trihydrate 11.1 mg, equivalent to 10 mg esomeprazole;
excipients: methacrylic acid and ethyl acrylate copolymer (1:1) 9.5 mg, talc 8.4 mg; sucrose, spherical granules (sugar, spherical granules) (size 0.250 - 0.355 mm) 7.4 mg, hyprolose 32.2 mg, hypromellose 1.7 mg, triethyl citrate 0.95 mg, magnesium stearate 0.65 mg, glycerol monostearate 40 -55 0.48 mg, Polysorbate 80 0.27 mg, dextrose 2813 mg, crospovidone 75 mg, xanthan gum 75 mg, anhydrous citric acid 4.9 mg, yellow iron oxide dye 1.8 mg.
Description
Pale yellow granules of various sizes (the main mass is finely divided granules and larger ones are pellets). Brownish granules may occur.

Pharmacodynamics. Esomeprazole is the S-isomer of omeprazole and reduces gastric acid secretion by specific inhibition of the proton pump in parietal cells.
stomach. S- and R-isomers of omeprazole have similar pharmacodynamic activity.
Mechanism of action
Esomeprazole is a weak base that passes into the active form in the highly acidic environment of the secretory tubules of the parietal cells of the gastric mucosa and inhibits the proton pump - the enzyme H + / K + - ATPase, while inhibiting both basal and stimulated secretion of hydrochloric acid.
Effect on gastric acid secretion
The action of esomeprazole develops within 1 hour after oral administration of 20 mg or 40 mg. With daily administration of the drug for 5 days at a dose of 20 mg once a day, the average maximum concentration of hydrochloric acid after stimulation with pentagastrin is reduced by 90% (when measuring the concentration of acid after 6-7 hours
after taking the drug on the 5th day of therapy). In patients with gastroesophageal reflux disease (GERD) and clinical symptoms, after 5 days of daily oral esomeprazole for
dose of 20 mg or 40 mg intragastric pH above 4 was maintained for, on average, 13 and 17 hours out of 24 hours. While taking esomeprazole at a dose of 20 mg per day, intragastric pH above 4 was maintained for at least 8, 12 and 16 hours in 76%, 54% and 24% of patients, respectively. For 40 mg esomeprazole, this ratio is 97%, 92% and 56%, respectively.
A correlation was found between the plasma concentration of the drug and inhibition of hydrochloric acid secretion (the AUC parameter (the area under the concentration-time curve) was used to estimate the concentration).
Therapeutic effect achieved as a result of inhibition of hydrochloric acid secretion
When taking Nexium® at a dose of 40 mg, healing occurs in approximately 78% of patients after 4 weeks of therapy and in 93% after 8 weeks of therapy.
Treatment with Nexium® at a dose of 20 mg 2 times a day in combination with appropriate antibiotics for one week leads to successful eradication of Helicobacter pylori in approximately 90% of patients.
Patients with uncomplicated peptic ulcer after a weekly eradication course do not require subsequent monotherapy with drugs that reduce the secretion of the gastric glands to heal the ulcer and eliminate symptoms.
Nexium® has been shown to be effective in bleeding from a peptic ulcer, confirmed by endoscopic examination.
Use in GERD in children (aged 1-11 years)
Healing, confirmed by endoscopic data, was observed in 93.3% of patients aged 1-11 years after 8 weeks of therapy with Nexium®. Patients weighing less than 20 kg took Nexium® at a daily dose of 5 mg or 10 mg, and patients weighing more than 20 kg at a daily dose of 10 mg or 20 mg.
Other effects associated with inhibition of hydrochloric acid secretion
During treatment with drugs that reduce the secretion of the gastric glands, the concentration of gastrin in plasma increases as a result of a decrease in the secretion of hydrochloric acid. Due to a decrease in the secretion of hydrochloric acid, the concentration of chromogranin A (CgA) increases. An increase in CgA concentration may affect the results of examinations for the detection of neuroendocrine tumors. To prevent this effect, it is necessary to temporarily stop taking esomeprazole 5 days before the study of CgA concentration.
In patients who have received esomeprazole for a long time, there is an increase in the number of enterochromaffin-like cells, probably associated with an increase in the concentration of gastrin in plasma.
In patients taking drugs that reduce the secretion of the gastric glands for a long period of time, the formation of glandular cysts in the stomach is more common. These phenomena are due to physiological changes as a result of a pronounced inhibition of the secretion of hydrochloric acid. The cysts are benign and regress.
The use of drugs that suppress the secretion of hydrochloric acid in the stomach, including proton pump inhibitors, is accompanied by an increase in the content of microbial flora in the stomach, which is normally present in the gastrointestinal tract. The use of proton pump inhibitors may lead to a slight increase in the risk of infections caused by Salmonella spp., Campylobacter spp. and probably Clostridium difficile in hospitalized patients.
Nexium® showed better efficacy compared to ranitidine in the healing of gastric ulcers in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2).
Nexium® showed high efficacy in the prevention of gastric and duodenal ulcers in patients treated with NSAIDs (age group over 60 years and / or with a history of peptic ulcer), including selective COX-2 inhibitors.

Pharmacokinetics. absorption and distribution. Esomeprazole is unstable in an acidic environment, therefore, tablets containing granules of the drug, the shell of which is resistant to the action of gastric juice, are used for oral administration. Under in vivo conditions, only a small part of esomeprazole is converted to the R-isomer. The drug is rapidly absorbed: the maximum plasma concentration is reached 1-2 hours after ingestion. The absolute bioavailability of esomeprazole after a single dose of 40 mg is 64% and increases to 89% against the background of daily administration once a day. For a dose of 20 mg of esomeprazole, these figures are 50% and 68%, respectively. The volume of distribution at steady state concentration in healthy people is approximately 0.22 l/kg of body weight. Esomeprazole binds to plasma proteins by 97%.
Eating slows down and reduces the absorption of esomeprazole in the stomach, but this does not significantly affect the effectiveness of inhibition of hydrochloric acid secretion.
Metabolism and excretion. Esomeprazole is metabolized with the participation of the cytochrome P450 system. The main part is metabolized with the participation of a specific polymorphic isoenzyme CYP2C19, with the formation of hydroxylated and desmethylated metabolites of esomeprazole. The metabolism of the remaining part is carried out by the CYP3A4 isoenzyme; in this case, a sulfo derivative of esomeprazole is formed, which is the main metabolite determined in plasma.
The parameters below reflect mainly the nature of the pharmacokinetics in patients with increased activity of the CYP2C19 isoenzyme.
The total clearance is approximately 17 l / h after a single dose of the drug and 9 l / h - after multiple doses. The elimination half-life is 1.3 hours when taken systematically once a day. The area under the concentration-time curve (AUC) increases with repeated administration of esomeprazole. The dose-dependent increase in AUC with repeated administration of esomeprazole is non-linear, which is a consequence of a decrease in first-pass metabolism through the liver, as well as a decrease in systemic clearance, probably caused by inhibition of the CYP2C19 isoenzyme by esomeprazole and / or its sulfo derivative. With daily intake once a day, esomeprazole is completely eliminated from the blood plasma between doses and does not accumulate.
The main metabolites of esomeprazole do not affect the secretion of gastric acid. When administered orally, up to 80% of the dose is excreted as metabolites in the urine, the rest is excreted in the faeces. Less than 1% of unchanged esomeprazole is found in the urine.
Features of pharmacokinetics in some groups of patients. Approximately 2.9±1.5% of the population has reduced activity of the CYP2C19 isoenzyme. In such patients, the metabolism of esomeprazole is mainly carried out as a result of the action of CYP3A4. With the systematic administration of 40 mg of esomeprazole once a day, the average AUC value is 100% higher than the value of this parameter in patients with increased activity of the CYP2C19 isoenzyme. The average values ​​of the maximum plasma concentrations in patients with reduced activity of the isoenzyme are increased by approximately 60%. These features do not affect the dose and route of administration of esomeprazole.
In elderly patients (71-80 years), the metabolism of esomeprazole does not undergo significant changes.
After a single dose of 40 mg of esomeprazole, the average AUC value in women is 30% higher than that in men. With daily administration of the drug once a day, there are no differences in pharmacokinetics in men and women. These features do not affect the dose and route of administration of esomeprazole.
In patients with mild to moderate hepatic insufficiency, the metabolism of esomeprazole may be impaired. In patients with severe hepatic insufficiency, the metabolic rate is reduced, which leads to an increase in the AUC value for esomeprazole by 2 times. For patients with severe hepatic insufficiency, the maximum daily dose of 20 mg should not be exceeded. When taken once a day, no accumulation of esomeprazole and its main metabolites was observed.
The study of pharmacokinetics in patients with renal insufficiency has not been conducted. Since not esomeprazole itself is excreted through the kidneys, but its metabolites, it can be assumed that the metabolism of esomeprazole in patients with renal insufficiency does not change.
In children aged 12-18 years, after repeated administration of 20 mg and 40 mg of esomeprazole, the AUC value and the time to reach the maximum concentration (tmax) in blood plasma were similar to the values ​​of AUC and tmax in adults.
In children aged 1-11 years, after repeated administration of 10 mg of esomeprazole, the AUC value was similar to the AUC value in adolescents and adults when taking 20 mg of esomeprazole.
In children aged 1-11 years, after repeated administration of 20 mg of esomeprazole, the AUC value was 6-11 times higher than the AUC value in adolescents and adults when taking 20 mg of esomeprazole.

GERD:
- treatment of erosive reflux esophagitis - long-term maintenance treatment after healing of erosive reflux esophagitis to prevent recurrence - symptomatic treatment of GERD

As part of combination therapy:
- treatment of duodenal ulcer associated with Helicobacter pylori
- prevention of recurrence of peptic ulcer associated with Helicobacter pylori
Long-term acid-suppressing therapy in patients who have had bleeding from a peptic ulcer (after intravenous use of drugs that reduce the secretion of the gastric glands to prevent relapse).

- healing of gastric ulcers associated with the use of NSAIDs
- prevention of gastric and duodenal ulcers associated with the use of NSAIDs in patients at risk
Zollinger-Ellison syndrome or other conditions characterized by pathological hypersecretion of the gastric glands, including idiopathic hypersecretion.

Nexium® in the dosage form of enteric-coated pellets and granules for oral suspension is intended mainly for pediatric patients and persons with difficulty swallowing.
inside. To take 10 mg of Nexium®, pour the contents of one package into a glass containing 15 ml of water. To take 20 mg of Nexium®, pour the contents of 2 packets into a glass containing 30 ml of water. To take 40 mg of Nexium®, pour the contents of 4 packets into a glass containing 60 ml of water. The contents of the glass should be mixed and wait a few minutes to form a suspension. The suspension can be taken orally immediately or within 30 minutes after preparation, stirring again before use. Then you should again add 15 ml of water to a glass, stir the rest and take it inside. Do not use sparkling water. Pellets and granules must not be chewed or crushed.
The suspension can be administered through a nasogastric tube. Instructions for the preparation and administration of the drug through a nasogastric tube are given in the section "Administration of the drug through a nasogastric tube".
Children 1-11 years old weighing ≥ 10 kg
GERD
Treatment of erosive reflux esophagitis: for patients weighing more than 10 kg, but less than 20 kg - 10 mg once a day for 8 weeks. For patients weighing 20 kg or more - 10 mg or 20 mg once a day for 8 weeks.
Symptomatic treatment of GERD: 10 mg once a day for up to 8 weeks.
The use of esomeprazole in doses greater than 1 mg/kg/day has not been studied.
Adults and children from 12 years old
GERD
Treatment of erosive reflux esophagitis: 40 mg once a day for 4 weeks.
An additional 4-week course of treatment is recommended in cases where, after the first course, healing of esophagitis does not occur or symptoms persist. Long-term maintenance treatment after healing of erosive reflux esophagitis to prevent recurrence: 20 mg once a day.
Symptomatic treatment of GERD: 20 mg once daily for patients without esophagitis. If after 4 weeks of treatment the symptoms do not disappear, an additional examination of the patient should be carried out. After the symptoms have been eliminated, you can switch to the regimen of taking the drug “as needed”, i.e. take Nexium® 20 mg once a day with the resumption of symptoms. For patients taking NSAIDs and at risk of developing gastric or duodenal ulcers, treatment on an "as needed" basis is not recommended.
adults
Peptic ulcer of the stomach and duodenum
As part of combination therapy for eradication with Helicobacter pylori:
Treatment of duodenal ulcer associated with Helicobacter pylori: Nexium® 20 mg, amoxicillin 1 g and clarithromycin 500 mg. All drugs are taken twice a day for 1 week.
prevention of recurrence of peptic ulcers associated with Helicobacter pylori: Nexium® 20 mg, amoxicillin 1 g and clarithromycin 500 mg. All drugs are taken twice a day for 1 week.
Long-term acid-suppressing therapy in patients who have had bleeding from a peptic ulcer (after intravenous use of drugs that reduce the secretion of the gastric glands to prevent recurrence):
Nexium® 40 mg 1 time per day for 4 weeks after the end of intravenous therapy with drugs that reduce the secretion of the gastric glands.
Patients taking NSAIDs for a long time:
- healing of gastric ulcers associated with taking NSAIDs: Nexium® 20 mg or 40 mg once a day. The duration of treatment is 4-8 weeks.
- prevention of gastric and duodenal ulcers associated with the use of NSAIDs: Nexium® 20 mg or 40 mg once a day.
Conditions associated with pathological hypersecretion of the gastric glands, including Zollinger-Ellison syndrome and idiopathic hypersecretion: The recommended initial dose is Nexium® 40 mg twice a day. In the future, the dose is selected individually, the duration of treatment is determined by the clinical picture of the disease. There is experience with the use of the drug in doses up to 120 mg 2 times a day.
Children under the age of 1 year or weighing less than 10 kg: Due to the lack of data on efficacy and safety, Nexium® should not be used in children under the age of 1 year or weighing less than 10 kg.
Renal insufficiency: dose adjustment of the drug is not required. However, experience with the use of Nexium® in patients with severe renal insufficiency is limited; in this regard, when prescribing the drug to such patients, care should be taken (see the section "Pharmacokinetics").
Hepatic insufficiency: with mild and moderate hepatic insufficiency, dose adjustment of the drug is not required. For patients with severe hepatic insufficiency, the maximum daily dose should not be exceeded - 10 mg for patients aged 1-11 years and 20 mg for patients over 12 years of age.
Elderly patients: dose adjustment of the drug is not required.
The introduction of the drug through a nasogastric tube:
1. To administer 10 mg of Nexium®, pour the contents of one package into a glass containing 15 ml of water.
2. To administer 20 mg of Nexium®, pour the contents of 2 packets into a glass containing 30 ml of water.
3. To administer 40 mg of Nexium®, pour the contents of 4 packets into a glass containing 60 ml of water.
4. Stir the contents of the beaker and wait a few minutes for a suspension to form.
5. Mix the suspension again and draw it into the syringe.
6. Enter the suspension immediately or within 30 minutes after preparation.
7. Draw another 15 ml (for a dose of 10 mg), or 30 ml (for a dose of 20 mg), or 60 ml (for a dose of 40 mg) of water into the syringe, shake the syringe and inject the rest of the suspension into the nasogastric tube.
Unused suspension should be destroyed.

In the presence of any alarming symptoms (for example, such as significant spontaneous weight loss, repeated vomiting, vomiting with blood or melena), as well as in the presence of a stomach ulcer (or if a stomach ulcer is suspected), the presence of a malignant neoplasm should be excluded, since treatment with Nexium ® can lead to a smoothing of symptoms and delay the diagnosis.
In rare cases, in patients who have taken omeprazole for a long time, a histological examination of biopsy specimens of the mucous membrane of the body of the stomach revealed atrophic.
Patients taking the drug for a long period (especially more than a year) should be under regular medical supervision.
Long-term use of the drug is not indicated for children and adolescents under the age of 12 years.
Patients taking Nexium "as needed" should be instructed to contact their physician if symptoms change. Taking into account fluctuations in the concentration of esomeprazole in plasma when prescribing therapy "as needed", the interaction of the drug with other drugs should be taken into account (see the section "Interaction with other drugs and other types of drug interactions"). When prescribing Nexium® for the eradication of Helicobacter pylori, the possibility of drug interactions for all components of triple therapy should be taken into account. Clarithromycin is a potent inhibitor of the CYP3A4 isoenzyme, therefore, when prescribing eradication therapy to patients receiving other drugs that are metabolized with the participation of the CYP3A4 isoenzyme (for example, cisapride), it is necessary to take into account possible contraindications and interactions of clarithromycin with these drugs. Nexium® contains sucrose and dextrose, so they are contraindicated in patients with hereditary fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency.
EFFECT ON ABILITY TO DRIVE AND OTHER MECHANISMS
Due to the fact that during therapy with Nexium®, blurred vision and drowsiness may be observed, care should be taken when driving vehicles and operating other mechanisms.

The following are the side effects that do not depend on the dosage regimen of the drug, noted with the use of the drug Nexium®, both during clinical trials and in post-marketing studies.
Often
(>1/100, <1/10)
Headache, abdominal pain, /vomiting,
Infrequently
(>1/1000, <1/100)
Dermatitis, itching, rash, drowsiness, insomnia, dizziness, dry mouth, blurred vision, peripheral, elevated liver enzymes
Rarely
(>1/10000, <1/1000)
Hypersensitivity reactions (eg, fever, angioedema, anaphylactic reaction/anaphylactic shock), (with or without jaundice), agitation, confusion, taste disturbance, gastrointestinal candidiasis, photosensitivity, malaise, sweating
Very rarely
(<1/10000)
Agranulocytosis, pancytopenia, aggressive behavior, in patients with liver disease, muscle weakness, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme,.

Effect of esomeprazole on the pharmacokinetics of other drugs. A decrease in the acidity of gastric juice during treatment with esomeprazole can lead to a change in the absorption of drugs, the absorption of which depends on the acidity of the environment. As with other drugs that suppress the secretion of hydrochloric acid or antacids, treatment with esomeprazole can lead to a decrease in the absorption of ketoconazole or itraconazole, as well as an increase in the absorption of digoxin. Co-administration of omeprazole 20 mg once daily with digoxin increases the bioavailability of digoxin by 10% (digoxin bioavailability increased by up to 30% in 20% of patients).
Omeprazole has been shown to interact with some antiretroviral drugs. The mechanisms and clinical significance of these interactions are not always known. An increase in pH during therapy with omeprazole may affect the absorption of antiretroviral drugs. Interaction at the level of the CYP2C19 isoenzyme is also possible. With the joint appointment of omeprazole and some antiretroviral drugs, such as atazanavir and nelfinavir, during therapy with omeprazole, there is a decrease in their serum concentration. Therefore, their simultaneous use is not recommended. Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a significant decrease in the bioavailability of atazanavir (area under the concentration-time curve, maximum (Cmax) and minimum (Cmin) concentrations decreased by approximately 75%). Increasing the dose of atazanavir to 400 mg did not compensate for the effect of omeprazole on the bioavailability of atazanavir.
With the simultaneous appointment of omeprazole and saquinavir, an increase in the concentration of saquinavir in serum was noted, when administered with some other antiretroviral drugs, their concentration did not change. Given the similar pharmacokinetic and pharmacodynamic properties of omeprazole and esomeprazole, co-administration of esomeprazole with antiretrovirals such as atazanavir and nelfinavir is not recommended.
Esomeprazole inhibits CYP2C19, the main isoenzyme involved in its metabolism. Accordingly, the combined use of esomeprazole with other drugs in the metabolism of which the CYP2C19 isoenzyme is involved, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., may lead to an increase in plasma concentrations of these drugs, which, in turn, may require dose reduction. This interaction is especially important to remember when prescribing Nexium® in the "as needed" mode. When co-administered 30 mg of esomeprazole and diazepam, which is a substrate of the CYP2C19 isoenzyme, there is a decrease in the clearance of diazepam by 45%.
The appointment of esomeprazole at a dose of 40 mg led to an increase in the residual concentration of phenytoin in patients with epilepsy by 13%. In this regard, it is recommended to control plasma concentrations of phenytoin at the beginning of treatment with esomeprazole and when it is canceled.
The administration of omeprazole at a dose of 40 mg once a day led to an increase in the area under the concentration-time curve and Cmax of voriconazole (CYP2C19 isoenzyme substrate) by 15% and 41%, respectively.
Co-administration of warfarin with 40 mg of esomeprazole does not lead to a change in coagulation time in patients taking warfarin for a long time. However, several cases of clinically significant increase in INR (international normalized ratio) have been reported with the combined use of warfarin and esomeprazole. It is recommended to control INR at the beginning and at the end of the combined use of esomeprazole and warfarin or other coumarin derivatives.
Esomeprazole, like omeprazole, inhibits the CYP2C19 isoenzyme. Co-administration of cilostazol and 40 mg of omeprazole leads to an increase in the pharmacokinetic parameters of cilostazol in healthy volunteers: Cmax and AUC by 18% and 26%, respectively. Similar parameters of one of the active metabolites of cilostazol increase by 29% and 69%, respectively.
Co-administration of cisapride with 40 mg of esomeprazole leads to an increase in the pharmacokinetic parameters of cisapride in healthy volunteers: AUC - by 32% and half-life by 31%, however, the maximum concentration of cisapride in plasma does not change significantly. A slight prolongation of the QT interval, which was observed with cisapride monotherapy, did not increase with the addition of Nexium® (see section "Special Instructions").
Nexium does not cause clinically significant changes in the pharmacokinetics of amoxicillin and quinidine.
Studies evaluating the short-term co-administration of esomeprazole and naproxen or rofecoxib did not reveal a clinically significant pharmacokinetic interaction.
Influence of drugs on the pharmacokinetics of esomeprazole.
Esomeprazole is metabolized by CYP2C19 and CYP3A4 isoenzymes. The combined use of esomeprazole with clarithromycin (500 mg 2 times a day), which inhibits the CYP3A4 isoenzyme, leads to an increase in the AUC of esomeprazole by 2 times. The combined use of esomeprazole and a combined inhibitor of CYP3A4 and CYP2C19 isoenzymes, for example, voriconazole, can lead to a more than 2-fold increase in the AUC value for esomeprazole. As a rule, in such cases, no dose adjustment of esomeprazole is required. Dose adjustment of esomeprazole may be required in patients with severe hepatic impairment and long-term use. Long-term use of the drug is not indicated for children and adolescents under the age of 12 years.
Drugs that induce CYP2C19 and CYP3A4 isoenzymes, such as rifampicin and St.

Hypersensitivity to esomeprazole, substituted benzimidazoles or other ingredients that make up the drug.
Hereditary fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency.
Children's age up to 1 year or body weight less than 10 kg (due to the lack of data on the efficacy and safety of the drug in this group of patients), children's age 1-11 years (for indications other than the treatment of erosive esophagitis and symptomatic treatment of GERD) and children over 12 years of age for indications other than GERD.
Esomeprazole should not be co-administered with atazanavir and nelfinavir (see section "Interaction with other medicinal products and other drug interactions").
With caution - severe (experience is limited).
USE DURING PREGNANCY AND BREASTFEEDING
Currently, there is not enough data on the use of the drug Nexium® during pregnancy. The results of epidemiological studies of omeprazole, which is a racemic mixture, showed no fetotoxic effect or impaired fetal development.
When esomeprazole was administered to animals, no direct or indirect negative effects on the development of the embryo or fetus were detected. The introduction of the racemic mixture of the drug also did not have any negative effect on animals during pregnancy, childbirth, and also during postnatal development.
The drug should be prescribed to pregnant women only if the expected benefit to the mother outweighs the possible risk to the fetus.
It is not known whether esomeprazole is excreted in breast milk, so Nexium® should not be administered during breastfeeding.

To date, extremely rare cases of intentional overdose have been described. Oral administration of esomeprazole at a dose of 280 mg was accompanied by general weakness and symptoms from the gastrointestinal tract. A single dose of 80 mg of Nexium® did not cause any negative effects. There is no known antidote for esomeprazole. Esomeprazole binds well to plasma proteins, so dialysis is ineffective. In case of overdose, symptomatic and general supportive treatment should be carried out.

coated tablets

One 20 mg tablet contains:

Active ingredient: 22.30 mg of esomeprazole magnesium trihydrate, which corresponds to 20 mg of esomeprazole.

Excipients: glyceryl monostearate 40-55 1.70 mg, hyprolose 8.10 mg, hypromellose 17.00 mg, iron dye red oxide (E172) 0.06 mg, iron dye yellow oxide (E 172) 0.02 mg, magnesium stearate 1 .20 mg, methacrylic and ethacrylic acid copolymer (1:1) 35.00 mg. cellulose microcrystalline 273.00. mg, paraffin 0.20 mg, macrogol 3.00 mg, polysorbate 80 0.62 mg, crospovidone. 5.70 mg sodium stearyl fumarate 0.57 mg, sucrose spherical granules - (sugar, spherical granules) (size 0.250-0.355 mm) 28.00 mg, titanium dioxide (E 171) 2.90 mg, talc 14.00 mg, triethyl citrate 10.00 mg;

One 40 mg tablet contains:

trihydrate, which corresponds to 40 mg of esomeprazole.

Excipients:glyceryl monostearate 40-55 2.30 mg, hyprolose 11.00 mg, hypromellose 26.00 mg, iron dye red oxide (E172) 0.45 mg, magnesium stearate 1.70 mg, methacrylic and ethacrylic acid copolymer (1: 1 ) 46.00 mg, microcrystalline cellulose 389.00 mg, paraffin 0.30 mg, macrogol 4.30 mg, polysorbate 80 1.10 mg, crospovidone 8.10 mg, sodium stearyl fumarate 0.81 mg, sucrose spherical granules (sugar , spherical granules) (size 0.250-0.355 mm) 30.00 mg, titanium dioxide (E 171) 3.80 mg, talc 20.00 mg, triethyl citrate 14.00 mg.

Tablets 20 mg: oblong, biconvex, light pink, film-coated tablet, engraved on one side with 20 mg, on the other side with .

Tablets 40 mg: oblong, biconvex, pink, film-coated tablet, engraved on one side with 40 mg, on the other side with .

Esomeprazole is the S-isomer of omeprazole and reduces gastric acid secretion by specific inhibition of the proton pump in gastric parietal cells. S- and R-isomer of omeprazole have similar pharmacodynamic activity.

Mechanism of action

Esomeprazole is a weak base that becomes active in the highly acidic environment of the secretory tubules of the parietal cells of the gastric mucosa and inhibits the proton pump - the enzyme H + / K + - ATPase, while inhibiting both basal and stimulated secretion of hydrochloric acid.

Influence on the secretion of acid in the stomach.

The action of esomeprazole develops within 1 hour after oral administration of 20 mg or 40 mg. With daily administration of the drug for 5 days at a dose of 20 mg once a day, the average maximum concentration of hydrochloric acid after stimulation with pentagastrin is reduced by 90% (when measuring the acid concentration 6-7 hours after taking the drug on the 5th day of therapy).

In patients with gastroesophageal reflux disease (GERD) and clinical symptoms, after 5 days of daily oral administration of esomeprazole at a dose of 20 mg or 40 mg, intragastric pH above 4 was maintained for, on average, 13 and 17 hours out of 24 hours. While taking esomeprazole at a dose of 20 mg per day, intragastric pH above 4 was maintained for at least 8, 12 and 16 hours in 76%, 54% and 24% of patients, respectively. For 40 mg esomeprazole, this ratio is 97%, 92% and 56%, respectively.

A correlation was found between the plasma concentration of the drug and the inhibition of hydrochloric acid secretion (the AUC parameter (the area under the concentration-time curve) was used to estimate the concentration).

Therapeutic effect achieved as a result of inhibition of hydrochloric acid secretion. When Nexium is taken at a dose of 40 mg, healing of reflux esophagitis occurs in approximately 78% of patients after 4 weeks of therapy and in 93% after 8 weeks of therapy.

Treatment with Nexium at a dose of 20 mg 2 times a day in combination with appropriate antibiotics for one week leads to successful eradication. Helicobacter pylori in approximately 90% of patients.

Patients with uncomplicated peptic ulcer after a weekly eradication course do not require subsequent monotherapy with drugs that reduce the secretion of the gastric glands to heal the ulcer and eliminate symptoms.

The efficacy of Nexium in peptic ulcer bleeding was shown in a study of patients with endoscopically confirmed peptic ulcer bleeding.

Other effects associated with inhibition of hydrochloric acid secretion. During treatment with drugs that reduce the secretion of the gastric glands, the concentration of gastrin in plasma increases as a result of a decrease in acid secretion.

In patients who have been treated for a long time, there is an increase in the number of enterochromaffin-like cells, probably associated with an increase in plasma gastrin concentration.

In patients taking drugs that reduce the secretion of the gastric glands for a long period of time, the formation of glandular cysts in the stomach is more common. These phenomena are due to physiological changes as a result of a pronounced inhibition of the secretion of hydrochloric acid. The cysts are benign and regress. The use of drugs that suppress the secretion of hydrochloric acid in the stomach, including proton pump inhibitors, is accompanied by an increase in the content of microbial flora in the stomach, which is normally present in the gastrointestinal tract. The use of proton pump inhibitors may lead to a slight increase in the risk of infectious diseases of the gastrointestinal tract caused by bacteria of the genus Salmonella spp. and Campylobacter spp.

In two comparative studies conducted with ranitidine, Nexium showed better efficacy in healing gastric ulcers in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors.

In two studies, Nexium showed high efficacy in preventing gastric and duodenal ulcers in patients treated with NSAIDs (age group over 60 years and / or with a history of peptic ulcer), including selective COX-2 inhibitors.

absorption and distribution. unstable in an acidic environment, therefore, for oral use, tablets containing granules of the drug, the shell of which is resistant to the action of gastric juice, are used. In conditions in vivo only a small part of esomeprazole is converted to the R-isomer. The drug is rapidly absorbed: the maximum plasma concentration is reached after 1 -

2 hours after taking. The absolute bioavailability of esomeprazole after a single dose of 40 mg is 64% and increases to 89% against the background of daily administration once a day. For a dose of 20 mg of esomeprazole, these figures are 50% and 68%, respectively. The volume of distribution at steady state concentration in healthy people is approximately

0.22 l/kg of body weight. binds to plasma proteins by 97%.

Eating slows down and reduces the absorption of esomeprazole in the stomach, but this does not significantly affect the effectiveness of inhibition of hydrochloric acid secretion.

Metabolism and excretion. undergoes metabolism with the participation of the cytochrome P450 system. The main part is metabolized with the participation of a specific polymorphic CYP2C19 isoenzyme, with the formation of hydroxylated and desmethylated metabolites of esomeprazole. The metabolism of the remaining part is carried out by the CYP3A4 isoenzyme; in this case, a sulfo derivative of esomeprazole is formed, which is the main metabolite determined in plasma.

The parameters below reflect mainly the nature of the pharmacokinetics in patients with increased activity of the CYP2C19 isoenzyme.

The total clearance is approximately 17 l / h after a single dose of the drug and 9 l / h - after multiple doses. The elimination half-life is 1.3 hours when taken systematically once a day. The area under the concentration-time curve (AUC) increases with repeated administration of esomeprazole. The dose-dependent increase in AUC with repeated administration of esomeprazole is non-linear, which is a consequence of a decrease in first-pass metabolism through the liver, as well as a decrease in systemic clearance, probably caused by inhibition of the CYP2C19 isoenzyme by esomeprazole and / or its sulfo derivative. With daily intake once a day, it is completely removed from the blood plasma in the interval between doses and does not accumulate.

The main metabolites of esomeprazole do not affect the secretion of gastric acid. When administered orally, up to 80% of the dose is excreted as metabolites in the urine, the rest is excreted in the faeces. Less than 1% of unchanged esomeprazole is found in the urine.

Features of pharmacokinetics in some groups of patients. Approximately 2.9±1.5% of the population has reduced activity of the CYP2C19 isoenzyme. In such patients, the metabolism of esomeprazole is mainly carried out as a result of the action of CYP3A4. With the systematic administration of 40 mg of esomeprazole once a day, the average AUC value is 100% higher than the value of this parameter in patients with increased activity of the CYP2C 19 isoenzyme. The average values ​​​​of maximum plasma concentrations in patients with reduced activity of the isoenzyme are increased by approximately 60%. These features do not affect the dose and route of administration of esomeprazole.

In elderly patients (71-80 years), the metabolism of esomeprazole does not undergo significant changes.

After a single dose of 40 mg of esomeprazole, the mean AUC in women is 30% higher than that in men. With daily administration of the drug once a day, there are no differences in pharmacokinetics in men and women. These features do not affect the dose and route of administration of esomeprazole.

In patients with mild to moderate hepatic insufficiency, the metabolism of esomeprazole may be impaired. In patients with severe hepatic insufficiency, the metabolic rate is reduced, which leads to a 2-fold increase in the AUC value for esomeprazole.

The study of pharmacokinetics in patients with renal insufficiency has not been conducted. Since not esomeprazole itself is excreted through the kidneys, but its metabolites, it can be assumed that the metabolism of esomeprazole in patients with renal insufficiency does not change.

In children aged 12-18 years, after repeated administration of 20 mg and 40 mg of esomeprazole, the AUC value and the time to reach the maximum concentration (tmax) in blood plasma were similar to the values ​​of AUC and tmax in adults.

Gastroesophageal reflux disease:

Treatment of erosive reflux esophagitis

Long-term maintenance treatment after healing of erosive reflux esophagitis to prevent recurrence

Symptomatic treatment of gastroesophageal reflux disease

Peptic ulcer of the stomach and duodenum As part of combination therapy:

Treatment of duodenal ulcer associated with Helicobacter pylori

prevention of recurrence of peptic ulcer associated with Helicobacter pylori

Long-term acid-suppressing therapy in patients who have had bleeding from a peptic ulcer (after intravenous use of drugs that reduce the secretion of the gastric glands to prevent relapse). Patients taking NSAIDs for a long time:

Healing of gastric ulcer associated with NSAIDs

Prevention of gastric and duodenal ulcers associated with the use of NSAIDs in patients at risk

Zollinger-Ellison syndrome or other conditions characterized by pathological hypersecretion of the gastric glands, including idiopathic hypersecretion.

Hypersensitivity to esomeprazole, substituted benzimidazoles or other ingredients that make up the drug.

Hereditary fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency.

Children under 12 years of age (due to the lack of data on the efficacy and safety of the drug in this group of patients) and children over 12 years of age for indications other than gastroesophageal reflux disease.

Esomeprazole should not be co-administered with atazanavir and nelfinavir (see section "Interaction with other medicinal products and other drug interactions").

Currently, there is not enough data on the use of Nexium during pregnancy. The results of epidemiological studies of omeprazole, which is a racemic mixture, showed no fetotoxic effect or impaired fetal development.

When esomeprazole was administered to animals, no direct or indirect negative effects on the development of the embryo or fetus were detected. The introduction of the racemic mixture of the drug also did not have any negative effect on animals during pregnancy, childbirth, and also during postnatal development.

The drug should be prescribed to pregnant women only if the expected benefit to the mother outweighs the possible risk to the fetus.

It is not known whether it is excreted in breast milk, so Nexium should not be given during breastfeeding.

inside. The tablet should be swallowed whole with liquid. Tablets should not be chewed or crushed.

For patients with difficulty swallowing, you can dissolve the tablets in half a glass of non-carbonated water (other liquids should not be used, as the protective shell of the microgranules may dissolve), stirring until the tablet disintegrates, after which the suspension of microgranules should be drunk immediately or within 30 minutes, after which again Fill the glass halfway with water, stir the rest and drink. Microgranules should not be chewed or crushed.

For patients who cannot swallow, the tablets should be dissolved in still water and administered via a nasogastric tube. It is important that the selected syringe and probe are suitable for this procedure. Instructions for the preparation and administration of the drug through a nasogastric tube are given in the section "Administration of the drug through a nasogastric tube."

Adults and children from 12 years old Gastroesophageal reflux disease

Treatment of erosive reflux esophagitis: 40 mg once a day for 4 weeks.

Long-term maintenance treatment after healing of erosive reflux esophagitis to prevent recurrence: 20 mg once a day.

Symptomatic treatment of gastroesophageal reflux disease: 20 mg once a day - for patients without esophagitis. If after 4 weeks of treatment the symptoms do not disappear, an additional examination of the patient should be carried out. After the symptoms have been eliminated, you can switch to the regimen of taking the drug “as needed”, i.e. take Nexium 20 mg once daily when symptoms recur. For patients taking NSAIDs and at risk of developing gastric or duodenal ulcers, treatment on an "as needed" basis is not recommended.

adults

Peptic ulcer of the stomach and duodenum As part of combination therapy for eradication with Helicobacter pylori".

treatment of duodenal ulcer associated with Helicobacter pylori: Nexium 20 mg, 1 g and 500 mg. All drugs are taken twice a day for 1 week, prevention of recurrence of peptic ulcers associated with Helicobacter pylori: Nexium 20 mg, 1 g and 500 mg. All drugs are taken twice a day for 1 week. Long-term acid-suppressing therapy in patients who have had bleeding from a peptic ulcer (after intravenous use of drugs that reduce the secretion of gastric glands to prevent recurrence)

Nexium 40 mg 1 time per day for 4 weeks after the end of intravenous therapy with drugs that reduce the secretion of the gastric glands.

Patients taking NSAIDs for a long time:

healing of gastric ulcer associated with taking NSAIDs: Nexium 20 mg or 40 mg once a day. The duration of treatment is 4-8 weeks, prevention of gastric and duodenal ulcers associated with taking NSAIDs: Nexium 20 mg or 40 mg once a day.

Conditions associated with pathological hypersecretion of the gastric glands, including Zollinger-Ellison syndrome and idiopathic hypersecretion:

The recommended starting dose is Nexium 40 mg twice daily. In the future, the dose is selected individually, the duration of treatment is determined by the clinical picture of the disease. There is experience with the use of the drug in doses up to 120 mg 2 times a day.

Kidney failure: dose adjustment of the drug is not required. However, experience with Nexium in patients with severe renal impairment is limited; in this regard, when prescribing the drug to such patients, care should be taken (see the Pharmacokinetics section).

Liver failure: with mild to moderate hepatic

insufficiency dose adjustment is not required. For patients with severe hepatic insufficiency, the maximum daily dose should not exceed 20 mg.

Elderly patients: dose adjustment of the drug is not required.

The introduction of the drug through a nasogastric tube

When prescribing the drug through a nasogastric tube

1. Place a tablet in the syringe and fill the syringe with 25 ml of water and approximately 5 ml of air. 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 tablet granules.

2. Shake the syringe immediately for about two minutes to dissolve the tablet.

3. Hold the syringe with the tip up and make sure the tip is not clogged.

4.Insert the tip of the syringe into the probe while continuing to hold it pointing upwards.

5. Shake the syringe and turn it upside down. Inject 5-10 ml of the dissolved drug into the tube immediately. After injection, return the syringe to its original position and shake (the syringe must be held with the tip up to avoid clogging the tip).

6. Turn the syringe upside down and inject another 5-10 ml of the drug into the probe. Repeat this operation until the syringe is empty.

7. In the case of the remainder of the drug in the form of sediment in the syringe, fill the syringe with 25 ml of water and 5 ml of air and repeat the operations described in paragraph 5.6. Some probes may require 50 ml of drinking water for this purpose.

The following are the side effects that do not depend on the dosage regimen of the drug, noted with the use of Nexium, both during clinical trials and in post-marketing studies.

To date, extremely rare cases of intentional overdose have been described. Oral administration of esomeprazole at a dose of 280 mg was accompanied by general weakness and symptoms from the gastrointestinal tract. A single dose of 80 mg of Nexium did not cause any negative consequences. There is no known antidote for esomeprazole. binds well to plasma proteins, so dialysis is ineffective. In case of overdose, symptomatic and general supportive treatment should be carried out.

Effect of esomeprazole on the pharmacokinetics of other drugs. A decrease in the acidity of gastric juice during treatment with esomeprazole can lead to a change in the absorption of drugs, the absorption of which depends on the acidity of the environment. , as antacids and other drugs that reduce the secretion of hydrochloric acid in the stomach, can lead to a decrease in the absorption of ketoconazole and itraconazole.

It has been shown to interact with. some antiretroviral drugs. The mechanisms and clinical significance of these interactions are not always known. An increase in pH during therapy with omeprazole may affect the absorption of antiretroviral drugs. Interaction at the level of CYP 2C 19 is also possible. With the joint appointment of omeprazole and certain antiretroviral drugs, such as and, against the background of omerpazole therapy, there is a decrease in their serum concentration. Therefore, their simultaneous use is not recommended. Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg to healthy volunteers resulted in a significant decrease in the bioavailability of atazanavir (area under the concentration-time curve, maximum (Cmax) and minimum (Cmin) concentrations decreased by approximately 75%). Increasing the dose of atazanavir to 400 mg did not compensate for the effect of omeprazole on the bioavailability of atazanavir.

With the simultaneous appointment of omeprazole and saquinavir, an increase in the concentration of saquinavir in serum was noted, when administered with some other antiretroviral drugs, their concentration did not change. Given the similar pharmacokinetic and pharmacodynamic properties of omeprazole and esomeprazole, the combined use of esomeprazole with antiretroviral drugs such as and is not recommended.

Esomeprazole inhibits CYP 2C 19, the main isoenzyme involved in its metabolism. Accordingly, the combined use of esomeprazole with other drugs in the metabolism of which CYP 2C 19 is involved, such as, and others, may lead to an increase in plasma concentrations of these drugs, which, in turn, may require a dose reduction. This interaction is especially important to remember when appointing Nexium in the "as needed" mode. When co-administered 30 mg of esomeprazole and diazepam, which is a substrate of cytochrome CYP 2C 19, there is a decrease in the clearance of diazepam by 45%.

The appointment of esomeprazole at a dose of 40 mg led to an increase in the residual concentration of phenytoin in patients with epilepsy by 13%. In this regard, it is recommended to control plasma concentrations of phenytoin at the beginning of treatment with esomeprazole and when it is canceled.

The administration of omeprazole at a dose of 40 mg once a day led to an increase in the area under the concentration-time curve and Cmax of voriconazole (CYP 2C 19 substrate) by 15% and 41%, respectively.

Co-administration of warfarin with 40 mg of esomeprazole does not lead to a change in coagulation time in patients taking it for a long time. However, several cases of a clinically significant increase in the INR index (international normalized ratio) have been reported with the combined use of warfarin and esomeprazole. It is recommended to control INR at the beginning and at the end of the combined use of esomeprazole and warfarin or other coumarin derivatives.

Co-administration of cisapride with 40 mg of esomeprazole leads to an increase in the pharmacokinetic parameters of cisapride in healthy volunteers: AUC - by 32% and half-life by 31%, however, the maximum concentration of cisapride in plasma does not change significantly. A slight prolongation of the QT interval, which was observed with cisapride monotherapy, did not increase with the addition of Nexium (see the section “Special Instructions”).

Nexium does not cause clinically significant changes in the pharmacokinetics of amoxicillin and quinidine.

Studies evaluating the short-term co-administration of esomeprazole and naproxen or rofecoxib did not reveal a clinically significant pharmacokinetic interaction.

Influence of drugs on the pharmacokinetics of esomeprazole.

CYP 2C 19 and CYP 3A 4 participate in the metabolism of esomeprazole. The combined use of esomeprazole with clarithromycin (500 mg 2 times a day), which inhibits CYP 3A 4, leads to an increase in the AUC value of esomeprazole by 2 times. The combined use of esomeprazole and a combined inhibitor of CYP 3A 4 and CYP 2C 19, for example, voriconazole, can lead to a more than 2-fold increase in the AUC value for esomeprazole. As a rule, in such cases, no dose adjustment of esomeprazole is required. Dose adjustment of esomeprazole may be required in patients with severe hepatic impairment and long-term use.

If there are any warning signs (eg, significant spontaneous weight loss, recurrent vomiting, dysphagia, vomiting of blood or melena), or if a stomach ulcer is present (or if a stomach ulcer is suspected), malignancy should be ruled out because treatment with Nexium can lead to a smoothing of symptoms and delay the diagnosis.

In rare cases, in patients who have been taking for a long time, a histological examination of biopsy specimens of the mucous membrane of the body of the stomach revealed atrophic gastritis.

Patients taking the drug for a long period (especially more than a year) should be under regular medical supervision.

Patients taking Nexium "as needed" should be instructed to contact their physician if symptoms change. Taking into account fluctuations in the concentration of esomeprazole in plasma when prescribing therapy "as needed", the interaction of the drug with other drugs should be taken into account (see the section "Interaction with other drugs and other types of drug interactions"). When appointing Nexium for eradication Helicobacterpylori the possibility of drug interactions for all components of triple therapy should be considered. is a potent inhibitor of CYP 3A 4, therefore, when prescribing eradication therapy to patients receiving other drugs that are metabolized with the participation of CYP 3A 4 (for example, cisapride), it is necessary to take into account possible contraindications and interactions of clarithromycin with these drugs.

The original drug Nexium (INN - esomeprazole) from the Anglo-Swedish pharmaceutical company Astra Zeneca belongs to an interesting class of drugs related to proton pump inhibitors (PPIs). Their history dates back to 1979, when the initiator of this group of medicines, omeprazole, was synthesized at the facilities of the same Astra Zeneca. Dashing trouble is the beginning: to date, there are already 5 generations of PPIs, among which Nexium (esomeprazole) is of particular interest. No matter how pathetic it sounds, but with the development of Nexium, a new step was taken in the development of APIs. The fact is that this drug has a higher bioavailability compared to omeprazole, and hence its advantage in therapeutic efficacy. In practice, this is manifested by a faster development of the pharmacological effect and its longer retention. The secret behind this key difference between Nexium and other PPIs is that it is an isomer. So called compounds that have the same molecular formula, but a different spatial structure. Despite the "passport" identity, one isomer can be much more effective than another. Omeprazole is a mixture of two isomers, while Nexium is represented by only one isomer, which acts most effectively: it is more actively involved in metabolic processes in the liver, it spreads faster along with the blood flow throughout the body, reaching the place of its direct therapeutic use - the parietal cells of the mucous membrane stomach.

For hypersecretory diseases, this means more controlled regulation of gastric pH, a higher percentage of successful outcomes of peptic ulcer disease in a shorter period of time, relief of reflux esophagitis, effective suppression of heartburn, and much more. In addition, Nexium undergoes biotransformation in the liver more slowly, which maintains the effective concentration of the drug in the blood for a longer time. In the treatment of reflux esophagitis, Nexium surpasses all other PPIs, curing it in an average of 30 days, while the same Omerpazole takes about 60 days to do this. And reducing the treatment time is also beneficial for the patient in terms of saving his personal budget.

Nexium is available in three dosage forms: tablets, lyophilisate for solution for intravenous administration and enteric-coated pellets for oral suspension. The dose and frequency of use is determined by the attending physician, depending on the disease, its severity and the individual characteristics of the patient.

Pharmacology

Esomeprazole is the S-isomer of omeprazole and reduces gastric acid secretion by specific inhibition of the proton pump in gastric parietal cells. The S- and R-isomers of omeprazole have similar pharmacodynamic activity.

Mechanism of action

Esomeprazole is a weak base that passes into the active form in the highly acidic environment of the secretory tubules of the parietal cells of the gastric mucosa and inhibits the proton pump - the enzyme H + / K + - ATPase, while inhibiting both basal and stimulated secretion of hydrochloric acid.

Influence on the secretion of hydrochloric acid in the stomach

The action of esomeprazole develops within 1 hour after oral administration of 20 mg or 40 mg. With daily administration of the drug for 5 days at a dose of 20 mg once a day, the average maximum concentration of hydrochloric acid after stimulation with pentagastrin is reduced by 90% (when measuring the acid concentration 6-7 hours after taking the drug on the 5th day of therapy). In patients with gastroesophageal reflux disease (GERD) and clinical symptoms, after 5 days of daily oral administration of esomeprazole at a dose of 20 mg or 40 mg, intragastric pH above 4 was maintained for, on average, 13 and 17 hours out of 24 hours. While taking esomeprazole at a dose of 20 mg per day, intragastric pH above 4 was maintained for at least 8, 12 and 16 hours in 76%, 54% and 24% of patients, respectively. For 40 mg esomeprazole, this ratio is 97%, 92% and 56%, respectively.

A correlation was found between the plasma concentration of the drug and inhibition of hydrochloric acid secretion (the AUC parameter (the area under the concentration-time curve) was used to estimate the concentration).

The therapeutic effect achieved as a result of inhibition of the secretion of hydrochloric acid. When Nexium is taken at a dose of 40 mg, healing of reflux esophagitis occurs in approximately 78% of patients after 4 weeks of therapy and in 93% after 8 weeks of therapy.

Treatment with Nexium at a dose of 20 mg 2 times a day in combination with appropriate antibiotics for one week leads to successful eradication of Helicobacter pylori in approximately 90% of patients.

Patients with uncomplicated peptic ulcer after a weekly eradication course do not require subsequent monotherapy with drugs that reduce the secretion of the gastric glands to heal the ulcer and eliminate symptoms.

The efficacy of Nexium in peptic ulcer bleeding was shown in a study of patients with endoscopically confirmed peptic ulcer bleeding.

Other effects associated with inhibition of hydrochloric acid secretion. During treatment with drugs that reduce the secretion of the gastric glands, the concentration of gastrin in plasma increases as a result of a decrease in acid secretion. Due to a decrease in the secretion of hydrochloric acid, the concentration of chromogranin A (CgA) increases. An increase in CgA concentration may affect the results of examinations for the detection of neuroendocrine tumors. To prevent this effect, therapy with proton pump inhibitors should be suspended 5-14 days before the study of CgA concentration. If during this time the concentration of CgA has not returned to normal, the study should be repeated.

In children and adult patients who have received esomeprazole for a long time, there is an increase in the number of enterochromaffin-like cells, probably associated with an increase in plasma gastrin concentration. This phenomenon has no clinical significance.

In patients taking drugs that reduce the secretion of the gastric glands for a long period of time, the formation of glandular cysts in the stomach is more common. These phenomena are due to physiological changes as a result of a pronounced inhibition of the secretion of hydrochloric acid. The cysts are benign and regress.

The use of drugs that suppress the secretion of hydrochloric acid in the stomach, including proton pump inhibitors, is accompanied by an increase in the content of microbial flora in the stomach, which is normally present in the gastrointestinal tract. The use of proton pump inhibitors may lead to a slight increase in the risk of infectious diseases of the gastrointestinal tract caused by bacteria of the genus Salmonella spp. and Campylobacter spp. and, in hospitalized patients, probably Clostridium difficile.

In two comparative studies conducted with ranitidine, Nexium showed better efficacy in healing gastric ulcers in patients treated with non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors. In two studies, Nexium showed high efficacy in preventing gastric and duodenal ulcers in patients treated with NSAIDs (age group over 60 years and / or with a history of peptic ulcer), including selective COX-2 inhibitors.

Pharmacokinetics

Absorption and distribution

Esomeprazole is unstable in an acidic environment, therefore, tablets containing granules of the drug, the shell of which is resistant to the action of gastric juice, are used for oral administration. Under in vivo conditions, only a small part of esomeprazole is converted to the R-isomer. The drug is rapidly absorbed: the maximum plasma concentration is reached 1-2 hours after ingestion. The absolute bioavailability of esomeprazole after a single dose of 40 mg is 64% and increases to 89% against the background of daily administration once a day. For a dose of 20 mg of esomeprazole, these figures are 50% and 68%, respectively. The volume of distribution at steady state concentration in healthy people is approximately 0.22 l/kg of body weight. Esomeprazole binds to plasma proteins by 97%.

Eating slows down and reduces the absorption of esomeprazole in the stomach, but this does not significantly affect the effectiveness of inhibition of hydrochloric acid secretion.

Metabolism and excretion

Esomeprazole is metabolized with the participation of the cytochrome P450 system. The main part is metabolized with the participation of a specific polymorphic isoenzyme CYP2C19, with the formation of hydroxylated and desmethylated metabolites of esomeprazole. The metabolism of the remaining part is carried out by the CYP3A4 isoenzyme; in this case, a sulfo derivative of esomeprazole is formed, which is the main metabolite determined in plasma.

The parameters below reflect mainly the nature of the pharmacokinetics in patients with increased activity of the CYP2C19 isoenzyme. The total clearance is approximately 17 l / h after a single dose of the drug and 9 l / h - after multiple doses. The elimination half-life is 1.3 hours when taken systematically once a day. The area under the concentration-time curve (AUC) increases with repeated administration of esomeprazole. The dose-dependent increase in AUC with repeated administration of esomeprazole is non-linear, which is a consequence of a decrease in first-pass metabolism through the liver, as well as a decrease in systemic clearance, probably caused by inhibition of the CYP2C19 isoenzyme by esomeprazole and / or its sulfo derivative. With daily intake once a day, esomeprazole is completely eliminated from the blood plasma between doses and does not accumulate.

The main metabolites of esomeprazole do not affect the secretion of gastric acid. When administered orally, up to 80% of the dose is excreted as metabolites in the urine, the rest is excreted in the faeces. Less than 1% of unchanged esomeprazole is found in the urine.

Features of pharmacokinetics in some groups of patients.

Approximately 2.9±1.5% of the population has reduced activity of the CYP2C19 isoenzyme. In such patients, the metabolism of esomeprazole is mainly carried out as a result of the action of CYP3A4. With the systematic administration of 40 mg of esomeprazole once a day, the average AUC value is 100% higher than the value of this parameter in patients with increased activity of the CYP2C19 isoenzyme. The average values ​​of the maximum plasma concentrations in patients with reduced activity of the isoenzyme are increased by approximately 60%. These features do not affect the dose and route of administration of esomeprazole. In elderly patients (71-80 years), the metabolism of esomeprazole does not undergo significant changes.

After a single dose of 40 mg of esomeprazole, the mean AUC in women is 30% higher than that in men. With daily administration of the drug once a day, there are no differences in pharmacokinetics in men and women. These features do not affect the dose and route of administration of esomeprazole. In patients with mild to moderate hepatic insufficiency, the metabolism of esomeprazole may be impaired. In patients with severe hepatic insufficiency, the metabolic rate is reduced, which leads to a 2-fold increase in the AUC value for esomeprazole.

The study of pharmacokinetics in patients with renal insufficiency has not been conducted. Since not esomeprazole itself is excreted through the kidneys, but its metabolites, it can be assumed that the metabolism of esomeprazole in patients with renal insufficiency does not change.

In children aged 12-18 years, after repeated administration of 20 mg and 40 mg of esomeprazole, the value of AUC and TC max in blood plasma was similar to the values ​​of AUC and TC max in adults.

Release form

Pink film-coated tablets, oblong, biconvex, debossed with "40 mg" on one side and "A/EI" in the form of a fraction on the other; on a break - white color with yellow impregnations (croup type).

Excipients: glyceryl monostearate 40-55 - 2.3 mg, hyprolose - 11 mg, hypromellose - 26 mg, iron dye red oxide (E172) - 450 mcg, magnesium stearate - 1.7 mg, copolymer of methacrylic and ethacrylic acids (1: 1) - 46 mg, microcrystalline cellulose - 389 mg, paraffin - 300 mcg, macrogol - 4.3 mg, polysorbate 80 - 1.1 mg, crospovidone - 8.1 mg, sodium stearyl fumarate - 810 mcg, sucrose spherical granules (sugar, spherical granules) (size 0.250-0.355 mm) - 30 mg, titanium dioxide (E171) - 3.8 mg, talc - 20 mg, triethyl citrate - 14 mg.

7 pcs. - aluminum blisters (1) - packs of cardboard.
7 pcs. - aluminum blisters (2) - packs of cardboard.
7 pcs. - aluminum blisters (4) - packs of cardboard.

Dosage

inside. The tablet should be swallowed whole with liquid. Tablets should not be chewed or crushed.

For patients with difficulty swallowing, you can dissolve the tablets in half a glass of non-carbonated water (other liquids should not be used, as the protective shell of the microgranules may dissolve), stirring until the tablet disintegrates, after which the suspension of microgranules should be drunk immediately or within 30 minutes, after which again Fill the glass halfway with water, stir the rest and drink. Microgranules should not be chewed or crushed.

For patients who cannot swallow, the tablets should be dissolved in still water and administered via a nasogastric tube. It is important that the selected syringe and probe are suitable for this procedure. Instructions for the preparation and administration of the drug through a nasogastric tube are given in the section "Administration of the drug through a nasogastric tube".

Adults and children from 12 years old

Gastroesophageal reflux disease

Treatment of erosive reflux esophagitis: 40 mg once a day for 4 weeks.

Long-term maintenance treatment after healing of erosive reflux esophagitis to prevent recurrence: 20 mg once a day.

Symptomatic treatment of gastroesophageal reflux disease: 20 mg once daily for patients without esophagitis. If after 4 weeks of treatment the symptoms do not disappear, an additional examination of the patient should be carried out. After eliminating the symptoms, you can switch to the regimen of taking the drug "as needed", i.e. take Nexium 20 mg once daily when symptoms recur. For patients taking NSAIDs and at risk of developing gastric or duodenal ulcers, treatment on an "as needed" basis is not recommended.

adults

As part of combination therapy for the eradication of Helicobacter pylori:

Treatment of duodenal ulcer associated with Helicobacter pylori: Nexium 20 mg, amoxicillin 1 g and clarithromycin 500 mg. All drugs are taken twice a day for 1 week.

Prevention of recurrence of peptic ulcers associated with Helicobacter pylori: Nexium 20 mg, amoxicillin 1 gi clarithromycin 500 mg. All drugs are taken twice a day for 1 week.

Long-term acid-suppressing therapy in patients who have had bleeding from a peptic ulcer (after intravenous use of drugs that reduce the secretion of gastric glands to prevent recurrence)

Nexium 40 mg 1 time per day for 4 weeks after the end of intravenous therapy with drugs that reduce the secretion of the gastric glands.

NSAID related gastric ulcer healing: Nexium 20 mg or 40 mg once daily. The duration of treatment is 4-8 weeks.

Prevention of gastric and duodenal ulcers associated with taking NSAIDs: Nexium 20 mg or 40 mg once a day.

Conditions associated with pathological hypersecretion of the gastric glands, including Zollinger-Ellison syndrome and idiopathic hypersecretion:

The recommended starting dose is Nexium 40 mg twice daily. In the future, the dose is selected individually, the duration of treatment is determined by the clinical picture of the disease. There is experience with the use of the drug in doses up to 120 mg 2 times a day.

Renal insufficiency: dose adjustment of the drug is not required. However, experience with Nexium in patients with severe renal impairment is limited; in this regard, when prescribing the drug to such patients, care should be taken (see the section "Pharmacokinetics").

Hepatic insufficiency: with mild and moderate hepatic insufficiency, dose adjustment of the drug is not required. For patients with severe hepatic insufficiency, the maximum daily dose should not exceed 20 mg.

Elderly patients: dose adjustment of the drug is not required.

The introduction of the drug through a nasogastric tube

When prescribing the drug through a nasogastric tube

1. Place a tablet in a syringe and fill the syringe with 25 ml of water and approximately 5 ml of air. 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 tablet granules.

2. Shake the syringe immediately for about two minutes to dissolve the tablet.

3. Hold the syringe with the tip up and check that the tip is not clogged.

4. Insert the tip of the syringe into the probe while continuing to hold it pointing up.

5. Shake the syringe and turn it upside down. Inject 5-10 ml of the dissolved drug into the tube immediately. After injection, return the syringe to its original position and shake (the syringe must be held with the tip up to avoid clogging the tip).

6. Turn the syringe upside down and inject another 5-10 ml of the drug into the probe. Repeat this operation until the syringe is empty.

7. In the case of the remainder of the drug in the form of sediment in the syringe, fill the syringe with 25 ml of water and 5 ml of air and repeat the operations described in paragraph 5.6. Some probes may require 50 ml of drinking water for this purpose.

Overdose

To date, extremely rare cases of intentional overdose have been described. Oral administration of esomeprazole at a dose of 280 mg was accompanied by general weakness and symptoms from the gastrointestinal tract. A single dose of 80 mg of Nexium did not cause any negative consequences.

The antidote for esomeprazole is unknown. Esomeprazole binds well to plasma proteins, so dialysis is ineffective. In case of overdose, symptomatic and general supportive treatment should be carried out.

Interaction

Effect of esomeprazole on the pharmacokinetics of other drugs.

Decreased secretion of hydrochloric acid in the stomach during treatment with esomeprazole and other proton pump inhibitors can lead to a decrease or increase in the absorption of drugs, the absorption of which depends on the acidity of the environment. Like other drugs that reduce gastric acidity, treatment with esomeprazole may lead to a decrease in the absorption of ketoconazole, itraconazole and erlotinib, and an increase in the absorption of drugs such as digoxin. Co-administration of omeprazole 20 mg once daily with digoxin increased the bioavailability of digoxin by 10% (bioavailability of digoxin increased by up to 30% in two out of ten patients).

Omeprazole has been shown to interact with some antiretroviral drugs. The mechanisms and clinical significance of these interactions are not always known. An increase in pH during therapy with omeprazole may affect the absorption of antiretroviral drugs. Interaction at the level of the CYP2C19 isoenzyme is also possible. With the combined use of omeprazole and some antiretroviral drugs, such as atazanavir and nelfinavir, during therapy with omeprazole, there is a decrease in their serum concentration. Therefore, their simultaneous use is not recommended. Co-administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg in healthy volunteers resulted in a significant decrease in the bioavailability of atazanavir (area under the concentration-time curve, Cmax and Cmin decreased by approximately 75%). Increasing the dose of atazanavir to 400 mg did not compensate for the effect of omeprazole on the bioavailability of atazanavir.

With the simultaneous use of omeprazole and saquinavir, an increase in serum concentrations of saquinavir was noted, when used with some other antiretroviral drugs, their concentration did not change. Given the similar pharmacokinetic and pharmacodynamic properties of omeprazole and esomeprazole, co-administration of esomeprazole with antiretrovirals such as atazanavir and nelfinavir is not recommended.

Esomeprazole inhibits CYP2C19, the main isoenzyme involved in its metabolism. Accordingly, the combined use of esomeprazole with other drugs in the metabolism of which the CYP2C19 isoenzyme is involved, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., may lead to an increase in plasma concentrations of these drugs, which, in turn, may require dose reduction. This interaction is especially important to remember when using Nexium in the "as needed" mode. When co-administered 30 mg of esomeprazole and diazepam, which is a substrate of the CYP2C19 isoenzyme, there is a decrease in the clearance of diazepam by 45%.

The use of esomeprazole at a dose of 40 mg led to an increase in the residual concentration of phenytoin in patients with epilepsy by 13%. In this regard, it is recommended to control plasma concentrations of phenytoin at the beginning of treatment with esomeprazole and when it is canceled.

The use of omeprazole at a dose of 40 mg once a day led to an increase in the area under the concentration-time curve and Cmax of voriconazole (CYP2C19 isoenzyme substrate) by 15% and 41%, respectively.

Co-administration of warfarin with 40 mg of esomeprazole does not lead to a change in coagulation time in patients taking warfarin for a long time. However, several cases of a clinically significant increase in the INR index (international normalized ratio) have been reported with the combined use of warfarin and esomeprazole. It is recommended to control INR at the beginning and at the end of the combined use of esomeprazole and warfarin or other coumarin derivatives.

Studies have shown a pharmacokinetic/pharmacodynamic interaction between clopidogrel (loading dose of 300 mg and maintenance dose of 75 mg/day) and esomeprazole (40 mg/day orally), which leads to a decrease in the exposure of the active metabolite of clopidogrel by an average of 40% and a decrease in maximum inhibition of ADP-induced platelet aggregation by an average of 14%.

The clinical significance of this interaction is not clear. In a prospective study in patients receiving placebo or omeprazole at a dose of 20 mg / day. concurrently with therapy with clopidogrel and acetylsalicylic acid (ACK), and in the analysis of clinical outcomes of large-scale randomized trials, there was no increase in the risk of cardiovascular complications with the combined use of clopidogrel and proton pump inhibitors, including esomeprazole.

The results of a number of observational studies are contradictory and do not give an unambiguous answer about the presence or absence of an increased risk of thromboembolic cardiovascular complications during the combined use of clopidogrel and proton pump inhibitors.

When using clopidogrel together with a fixed combination of 20 mg of esomeprazole and 81 mg of ASA, the exposure of the active metabolite of clopidogrel decreased by almost 40% compared with clopidogrel monotherapy, while the maximum levels of inhibition of ADP-induced platelet aggregation were the same, which is probably associated with simultaneous administration ASA at a low dose.

The use of omeprazole at a dose of 40 mg led to an increase in Cmax and AUC (area under the concentration-time curve) of cilostazol by 18% and 26%, respectively; for one of the active metabolites of cilostazol, the increase was 29% and 69%, respectively.

Co-administration of cisapride with 40 mg of esomeprazole leads to an increase in the pharmacokinetic parameters of cisapride in healthy volunteers: AUC - by 32% and half-life by 31%, however, the maximum concentration of cisapride in plasma does not change significantly. A slight prolongation of the QT interval, which was observed with cisapride monotherapy, did not increase with the addition of Nexium (see section "Special Instructions").

With the simultaneous use of esomeprazole and tacrolimus, an increase in the concentration of tacrolimus in the blood serum was noted.

In some patients, an increase in the concentration of methotrexate was noted against the background of joint use with proton pump inhibitors. When using high doses of methotrexate, the possibility of temporary withdrawal of esomeprazole should be considered.

Nexium does not cause clinically significant changes in the pharmacokinetics of amoxicillin and quinidine.

Studies evaluating the short-term co-administration of esomeprazole and naproxen or rofecoxib did not reveal a clinically significant pharmacokinetic interaction.

Influence of drugs on the pharmacokinetics of esomeprazole.

Esomeprazole is metabolized by CYP2C19 and CYP3A4 isoenzymes. The combined use of esomeprazole with clarithromycin (500 mg 2 times a day), which inhibits the CYP3A4 isoenzyme, leads to an increase in the AUC value of esomeprazole by 2 times. The combined use of esomeprazole and a combined inhibitor of CYP3A4 and CYP2C19 isoenzymes, for example, voriconazole, can lead to a more than 2-fold increase in the AUC value for esomeprazole. As a rule, in such cases, no dose adjustment of esomeprazole is required. Dose adjustment of esomeprazole may be required in patients with severe hepatic impairment and long-term use.

Drugs that induce CYP2C19 and CYP3A4 isoenzymes, such as rifampicin and St.

Side effects

The following are the side effects that do not depend on the dosage regimen of the drug, noted with the use of Nexium, both during clinical trials and in post-marketing studies. The frequency of side effects is given as the following gradation: very often (≥1/10); often (≥1/100,<1/10); нечасто (≥1/1000, <1/100); редко (≥1/10000, <1/1000); очень редко (<1/10000).

From the skin and subcutaneous tissues

Uncommon: dermatitis, pruritus, rash, urticaria;

Rare: alopecia, photosensitivity;

Very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

From the musculoskeletal and connective tissue

Rare: arthralgia, myalgia;

Very rare: muscle weakness.

From the side of the nervous system

Often: headache;

Uncommon: dizziness, paresthesia, drowsiness;

Rare: taste disturbance.

Mental disorders

Uncommon: insomnia;

Rare: depression, agitation, confusion;

Very rare: hallucinations, aggressive behavior.

From the gastrointestinal tract

Often: abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting;

Uncommon: dry mouth;

Rare: stomatitis, candidiasis of the gastrointestinal tract;

Very rare: microscopic colitis (histologically confirmed).

From the side of the liver and biliary tract

Infrequently: increased activity of "liver" enzymes;

Rare: hepatitis (with or without jaundice);

Very rare: liver failure, encephalopathy in patients with liver disease.

From the genital organs and mammary gland

Very rare: gynecomastia.

From the blood and lymphatic system

Rare: leukopenia, thrombocytopenia;

Very rare: agranulocytosis, pancytopenia.

From the side of the immune system

Rare: hypersensitivity reactions (eg, fever, angioedema, anaphylactic reaction/anaphylactic shock).

From the respiratory system, chest organs and mediastinum

Rare: bronchospasm.

From the side of the kidneys and urinary tract

Very rare: interstitial nephritis.

From the organ of vision

Rare: blurred vision.

From the side of metabolism and nutrition

Uncommon: peripheral edema;

Rare: hyponatremia;

Very rare: hypomagnesemia; hypocalcemia due to severe hypomagnesemia, hypokalemia due to hypomagnesemia.

General disorders

Rarely: malaise, sweating.

Indications

Gastroesophageal reflux disease:

• treatment of erosive reflux esophagitis;
• long-term maintenance treatment after healing of erosive reflux esophagitis to prevent recurrence;
• symptomatic treatment of gastroesophageal reflux disease;

Peptic ulcer of the stomach and duodenum

As part of combination therapy:

• treatment of duodenal ulcer associated with Helicobacter pylori;
• prevention of recurrence of peptic ulcer associated with Helicobacter pylori.

Long-term acid-suppressing therapy in patients who have had bleeding from a peptic ulcer (after intravenous use of drugs that reduce the secretion of the gastric glands to prevent relapse).

Patients taking NSAIDs for a long time:

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

Zollinger-Ellison syndrome or other conditions characterized by pathological hypersecretion of the gastric glands, including idiopathic hypersecretion.

Contraindications

• hypersensitivity to esomeprazole, substituted benzimidazoles or other ingredients that make up the drug;
• hereditary fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency;
• children under 12 years of age (due to the lack of data on the efficacy and safety of the drug in this group of patients) and children over 12 years of age for indications other than gastroesophageal reflux disease;
• Esomeprazole should not be co-administered with atazanavir and nelfinavir (see section "Interaction with other medicinal products and other drug interactions").

With caution: severe renal failure (experience is limited).

Application features

Use during pregnancy and lactation

Currently, there is not enough data on the use of Nexium during pregnancy. The results of epidemiological studies of omeprazole, which is a racemic mixture, showed no fetotoxic effect or impaired fetal development.

When esomeprazole was administered to animals, no direct or indirect negative effects on the development of the embryo or fetus were detected. The introduction of the racemic mixture of the drug also did not have any negative effect on animals during pregnancy, childbirth, and also during postnatal development.

The drug should be prescribed to pregnant women only if the expected benefit to the mother outweighs the possible risk to the fetus.

It is not known whether esomeprazole is excreted in breast milk, so Nexium should not be administered during breastfeeding.

Application for violations of liver function

With mild and moderate hepatic insufficiency, dose adjustment of the drug is not required. For patients with severe hepatic insufficiency, the maximum daily dose should not exceed 20 mg.

Application for violations of kidney function

Dose adjustment of the drug is not required. However, experience with Nexium in patients with severe renal impairment is limited; in this regard, when prescribing the drug to such patients, care should be taken (see the section "Pharmacokinetics").

Use in children

special instructions

If there are any warning signs (eg, significant spontaneous weight loss, recurrent vomiting, dysphagia, vomiting of blood or melena), or if a stomach ulcer is present (or if a stomach ulcer is suspected), malignancy should be ruled out because treatment with Nexium can lead to a smoothing of symptoms and delay the diagnosis.

In rare cases, in patients who have taken omeprazole for a long time, a histological examination of biopsy specimens of the gastric mucosa of the body of the stomach revealed atrophic gastritis.

Patients taking the drug for a long period (especially more than a year) should be under regular medical supervision. Patients taking Nexium "as needed" should be instructed to contact their physician if symptoms change. Taking into account fluctuations in the concentration of esomeprazole in plasma when prescribing therapy "as needed", the interaction of the drug with other drugs should be taken into account (see the section "Interaction with other drugs and other types of drug interactions"). When appointing Nexium for the eradication of Helicobacter pylori, the possibility of drug interactions for all components of triple therapy should be taken into account. Clarithromycin is a potent inhibitor of CYP3A4, therefore, when prescribing eradication therapy to patients receiving other drugs that are metabolized with the participation of CYP3A4 (for example, cisapride), possible contraindications and interactions of clarithromycin with these drugs should be taken into account.

Nexium tablets contain sucrose, so they are contraindicated in patients with hereditary fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency.

Studies have shown a pharmacokinetic/pharmacodynamic interaction between clopidogrel (loading dose of 300 mg and maintenance dose of 75 mg/day) and esomeprazole (40 mg/day orally), which leads to a decrease in exposure to the active metabolite of clopidogrel by an average of 40% and a decrease in the maximum inhibition of ADP-induced platelet aggregation by an average of 14%. Therefore, the simultaneous use of esomeprazole and clopidogrel should be avoided (see section "Interaction with other medicinal products and other types of drug interactions").

Separate observational studies indicate that proton pump inhibitor therapy may slightly increase the risk of osteoporosis-related fractures, but other similar studies have not noted an increase in risk.

In randomized, double-blind, controlled clinical trials of omeprazole and esomeprazole, including two open-label studies of long-term therapy (more than 12 years), the association of fractures due to osteoporosis with the use of proton pump inhibitors has not been confirmed.

Although a causal relationship between the use of omeprazole/esomeprazole and fractures due to osteoporosis has not been established, patients at risk of developing osteoporosis or fractures due to it should be under appropriate clinical supervision.

Influence on the ability to drive vehicles and control mechanisms

Due to the fact that during therapy with Nexium dizziness, blurred vision and drowsiness may occur, care should be taken when driving vehicles and other mechanisms.