Nexium - instructions for use, doses, side effects, contraindications

Excipients: glyceryl monostearate 40-55 1.70 mg, giprolose 8.10 mg, hypromellose 17.00 mg, iron dye red oxide (E172) 0.06 mg, iron dye oxide yellow (E 172) 0.02 mg, magnesium stearate 1 , 20 mg, methacrylic and ethacrylic acid copolymer (1: 1) 35.00 mg ,. microcrystalline cellulose 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:

Active substance: 44,50 mg of esomeprazole magnesium

trihydrate, corresponding to 40 mg of esomeprazole.

Excipients: glyceryl monostearate 40-55 2.30 mg, giprolose 11.00 mg, hypromellose 26.00 mg, iron dye red oxide (E172) 0.45 mg, magnesium stearate 1.70 mg, methacrylic acid 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.

Description:

Tablets 20 mg: oblong biconvex tablet light pink, coated, on the one hand engraving 20 mG, on the other hand - .

Tablets 40 mg: oblong biconvex tablet pink, coated, on the one hand engraving 40 mG, on the other hand - .

Pharmacotherapeutic group:glands of the stomach secretion-lowering agent - proton pump inhibitor

ATX: & nbsp

A.02.B.C.05 Esomeprazole

Pharmacodynamics:

Esomeprazole is S-isomer of omeprazole and reduces the secretion of hydrochloric acid in the stomach by specifically inhibiting the proton pump in parietal cells of the stomach. S- and R-isomer of omeprazole have similar pharmacodynamic activity.

Mechanism of action

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

Effect 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 intake 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 esomeprazole at a dose of 20 mg or 40 mg, the intragastric pH above 4 was maintained for an average of 13 and 17 hours out of 24 hours.Against the background of taking esomeprazole at a dose of 20 mg per day, the 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 of esomeprazole, this ratio is 97%, 92% and 56%, respectively.

A correlation was found between plasma concentration in the plasma and inhibition of hydrochloric acid secretion (the concentration AUC (area under the curve "concentration - time").

The therapeutic effect achieved by inhibiting the secretion of hydrochloric acid. When Nexium is taken in a dose of 40 mg, the 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 twice a day in combination with appropriate antibiotics for one week leads to successful eradication Helicobacter pylori in about 90% of patients.

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

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

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

Patients who received long-term esomeprazole, there is an increase in the number of enterochromaffin-like cells, probably associated with an increase in the concentration of gastrin in the plasma.

In patients taking drugs that reduce the secretion of the glands of the stomach, for a long period of time, the formation of glandular cysts in the stomach is more often noted. These phenomena are caused by physiological changes as a result of pronounced inhibition of the secretion of hydrochloric acid. Cysts are benign and undergo reverse development. The use of drugs suppressing the secretion of hydrochloric acid in the stomach, including proton pump inhibitors, is accompanied by an increase in stomach content in the microbial flora normally present in the gastrointestinal tract. The use of proton pump inhibitors can 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 with ranitidine, Nexium showed better efficacy in healing gastric ulcers in patients receiving non-steroidal anti-inflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase-2 (COX-2).

In two studies, Nexium showed high efficacy in the prevention of gastric and duodenal ulcers in patients who received NSAIDs (age group over 60 years and / or peptic ulcer in the anamnesis), including selective inhibitors of COX-2.

Pharmacokinetics:

Absorption and distribution. Esomeprazole is unstable in an acidic medium, therefore for oral use, tablets are used containing granules of the preparation, the shell of which is resistant to the action of gastric juice. In conditions in vivo Only a small fraction of esomeprazole is converted into Risomer. The drug is quickly absorbed: the maximum concentration in the plasma is achieved after 1 -

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

0, 22 l / kg body weight. Esomeprazole binds to plasma proteins by 97%.

Eating slows and reduces absorption of esomeprazole in the stomach, but this does not have a significant effect on the inhibition of hydrochloric acid secretion.

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

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

The total clearance is approximately 17 l / h after a single dose and 9 l / h - after repeated administration.The half-life is 1.3 hours with a systematic admission once a day. Area under the curve "concentration-time" (AUC) increases with repeated use of esomeprazole. Dose-dependent increase AUC with repeated administration of esomeprazole is non-linear, which is a consequence of a decrease in metabolism during the "first passage" through the liver, as well as a decrease in systemic clearance, probably caused by inhibition of the isoenzyme CYP2C19 esomeprazole and / or its sulfo derivative. With daily intake once a day esomeprazole completely removed from the blood plasma during a break between doses and does not cumulate.

The main metabolites of esomeprazole do not affect the secretion of gastric acid. When administered orally, up to 80% of the dose is excreted in the form of metabolites with urine, the rest is excreted with feces. In urine, less than 1% of unchanged esomeprazole is found.

Peculiarities of pharmacokinetics in some groups of patients. Approximately 2.9 ± 1.5% of the population has decreased isoenzyme activity CYP2C19. In such patients, the metabolism of esomeprazole is mainly due to the action of CYP3A4. With the systematic administration of 40 mg of esomeprazole, once a day, the mean AUC 100% higher than this parameter in patients with increased isoenzyme activity CYP2C19. Mean values of maximum plasma concentrations in patients with reduced isoenzyme activity were increased by approximately 60%. These features do not affect the dose and method of use of esomeprazole.

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

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

In patients with mild and 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 value AUC for esomeprazole 2 times.

The study of pharmacokinetics in patients with renal insufficiency was not carried out.Because the kidneys exclude not the most esomeprazole, 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 AUC and time to reach the maximum concentration (tmax) in blood plasma was similar to the values AUC and tmax in adults.

Indications:

Gastroesophageal reflux disease:

- treatment of erosive reflux esophagitis

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

- symptomatic treatment of gastroesophageal reflux disease

Stomach ulcer and duodenal ulcer As part of combination therapy:

- treatment of duodenal ulcers associated with Helicobacter pylori

prevention of recurrences of peptic ulcers associated with Helicobacter pylori

Long-term acid-suppressing therapy in patients who underwent bleeding from a peptic ulcer (after intravenous administration of drugs that reduce the secretion of the glands of the stomach, for the prevention of recurrence). Patients taking long-term NSAIDs:

- healing of gastric ulcer associated with the intake of NSAIDs

- prevention of gastric ulcer and duodenal ulcer associated with the intake of NSAIDs in patients at risk

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

Contraindications:

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

Hereditary intolerance to fructose, glucose-galactose malabsorption or sugar-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 on other indications other than gastroesophageal reflux disease.

Esomeprazole should not be taken together with atazanavir and nelfinavir (see section "Interaction with other drugs and other types of drug interactions").

Carefully:severe renal failure (experience with use is limited).

Pregnancy and lactation:

At present, there is insufficient 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.

With the introduction of esomeprazole, no direct or indirect adverse effects on the development of the embryo or fetus have been identified in animals. The introduction of the racemic mixture of the preparation also did not have any negative effect on animals during pregnancy, childbirth, and also during postnatal development.

Prescribe the drug to pregnant women only if the expected benefit to the mother exceeds the possible risk to the fetus.

It is not known whether esomeprazole with breast milk, so do not prescribe Nexium during breastfeeding.

Dosing and Administration:

Inside. The tablet should be swallowed whole, washed down with liquid. Tablets can not be chewed or crushed.

For patients with difficulty swallowing, you can dissolve tablets in half a glass of still water (do not use other liquids,since the protective shell of microgranules can dissolve), stirring up the disintegration of the tablet, after which the slurry of microgranules should be drunk immediately or within 30 minutes, then again fill the glass with water halfway, stir the remainders and drink. Do not chew or grind microgranules.

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

Adults and children from the age of 12 Gastroesophageal reflux disease

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

An additional 4-week course of treatment is recommended in cases when after the first course of healing the esophagitis does not come or the symptoms remain.

Long-term maintenance treatment after healing of erosive reflux- esophagitis to prevent relapse: 20 mg once daily.

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 eliminating the symptoms, you can go to the drug intake mode "if necessary", i.e. Take Nexium 20 mg once a day with the resumption of symptoms. For patients taking NSAIDs and those at risk of developing gastric or duodenal ulcers, treatment is not recommended if necessary.

Adults

Stomach ulcer and duodenal ulcer As part of a combination therapy for eradication with Helicobacter pylori '.

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

Nexium 40 mg once a day for 4 weeks after the end of intravenous therapy with drugs that reduce the secretion of the glands of the stomach.

Patients taking long-term NSAIDs:

healing of gastric ulcer associated with the intake of NSAIDs: Nexium 20 mg or 40 mg once daily. Duration of treatment is 4-8 weeks, prevention of gastric ulcer and duodenal ulcer associated with the intake of NSAIDs: Nexium 20 mg or 40 mg once a day.

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

The recommended initial 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 an experience of using the drug in doses up to 120 mg twice a day.

Renal insufficiency: dosage adjustment is not required. However, the experience of using Nexium in patients with severe renal insufficiency is limited; Therefore, when prescribing the drug, such patients should be careful (see section "Pharmacokinetics").

Liver failure: with mild and moderate hepatic

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

Older patients: dosage adjustment is not required.

Administration of the drug through a nasogastric tube

When prescribing the drug through a nasogastric tube

1. Place the tablet in a syringe and fill the syringe with 25 ml of water and about 5 ml of air. For some probes, dilution of the preparation in 50 ml of drinking water may be required in order to prevent the probe from clogging the pellets with a tablet.

2. Immediately shake the syringe for about two minutes to dissolve the tablet.

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

4. Insert the tip of the syringe into the probe, continuing to hold it pointed upwards.

5. Shake the syringe and flip it down with a tip. Immediately insert 5-10 ml of dissolved drug into the probe. After the injection, return the syringe to its previous position and shake it (the syringe should be held up by the tip to avoid clogging the tip).

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

7. In case of the remainder of the drug in the form of a sludge in a syringe, fill the syringe with 25 ml of water and 5 ml of air and repeat the operations described in paragraph 5.6. For some probes, 50 ml of drinking water may be needed for this purpose.

Side effects:

Below are the side effects that are independent of the dosing regimen of the drug, noted with the use of Nexium, both during clinical trials and in post-marketing studies.

Often (> 1/100, <1/10)	Headache, abdominal pain, diarrhea, flatulence, nausea / vomiting, constipation
Infrequently (> 1/1000, <1/100)	Dermatitis, itching, rash, hives, drowsiness, insomnia, dizziness, paresthesia, dry mouth, blurred vision, peripheral edema, increased activity of "liver" enzymes
Rarely (>1/10000, <1/1000)	Hypersensitivity reactions (eg, fever, angioedema, anaphylactic reaction / anaphylactic shock), bronchospasm, hepatitis (with or without jaundice), arthralgia, myalgia, leukopenia, thrombocytopenia, depression, hyponatremia, agitation, confusion, taste disorder, stomatitis, candidiasis gastrointestinal - intestinal tract, alopecia, photosensitivity, malaise, sweating
Very rarely (<1/10000)	Agranulocytosis, pancytopenia, hallucinations, aggressive behavior, hepatic insufficiency, encephalopathy in patients with liver disease, muscle weakness, interstitial nephritis, gynecomastia, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme

Overdose:

At the moment, very rare cases of deliberate overdose are described. Oral administration of esomeprazole at a dose of 280 mg was accompanied by general weakness and symptoms from the gastrointestinal tract. One-time intake of 80 mg of Nexium did not cause any negative consequences. The antidote of esomeprazole is unknown. Esomeprazole binds well to plasma proteins, so dialysis is ineffective. In case of an overdose, it is necessary to carry out symptomatic and general supportive treatment.

Interaction:

The effect of esomeprazole on the pharmacokinetics of other drugs. Reduction of acidity of gastric juice against the background of treatment with esomeprazole may lead to a change in the absorption of drugs, the absorption of which depends on the acidity of the medium. Esomeprazole, like 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 was shown that omeprazole interacts with. some antiretroviral drugs. The mechanisms and the clinical significance of these interactions are not always known. An increase in pH on the background of omeprazole therapy may affect the absorption of antiretroviral drugs. It is also possible to interact at the level CYP2C19. When co-prescribing omeprazole and some antiretroviral drugs, such as atazanavir and nelfinavir, against the background of therapy with omepazolom, there is a decrease in their concentration in the serum. Therefore, their simultaneous application is not recommended. The simultaneous 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, maximal (Stach) and minimal (Cmin) concentrations decreased by approximately 75%). An increase in the dose of atazanavir to 400 mg did not compensate for the effects of omeprazole on the bioavailability of atazanavir.

With the simultaneous administration of omeprazole and saquinavir, an increase in the concentrationsaquinavir in serum, 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 atazanavir and nelfinavir, Not recommended.

Esomeprazole inhibits CYP2C19 - the main isoenzyme involved in its metabolism. Accordingly, the joint use of esomeprazole with other drugs in the metabolism of which takes part CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin , etc., can lead to an increase in the concentrations of these drugs in the plasma, which, in turn, may require a dose reduction. It is especially important to remember this interaction when appointing Nexium in the "if necessary" mode. With the joint intake of 30 mg of esomeprazole and diazepam, which is a substrate of cytochrome CYP2C19, there is a decrease in clearance of diazepam by 45%.

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

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

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

Joint use of cisapride with 40 mg of esomeprazole leads to an increase in the pharmacokinetic parameters of cisapride in healthy volunteers: AUC - 32% and half-life at 31%, but the maximum concentration of cisapride in the plasma does not change significantly. Slight lengthening of the interval QT, which was observed with monotherapy with cisapride, did not increase with 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 joint use of esomeprazole and naproxen or rofecoxib have not revealed a clinically significant pharmacokinetic interaction.

Effect of drugs on the pharmacokinetics of esomeprazole.

In the metabolism of esomeprazole take part CYP2C19 and CYP3A4. Joint use of esomeprazole with clarithromycin (500 mg 2 times a day), which inhibits CYP3A4, leads to an increase in the value AUC esomeprazole 2 times. Joint use of esomeprazole and a combined inhibitor CYP3A4 and CYP2C19, for example, voriconazole, can lead to more than 2-fold increase in the value AUC for esomeprazole. As a rule, in such cases, dosage correction of esomeprazole is not required. Correction of the dose of esomeprazole may be required in patients with severe impairment of liver function and with prolonged use.

Special instructions:

In the presence of any anxiety symptoms (for example, such as significant spontaneous weight loss, repeated vomiting, dysphagia, vomiting with a trace of blood or melena),and in the presence of a stomach ulcer (or suspected gastric ulcer), the presence of malignant neoplasm should be excluded, since treatment with Nexium can lead to a smoothing of the symptoms and delay the diagnosis.

In rare cases, patients who have been taking long-term omeprazole, 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 the symptoms change. Taking into account the fluctuations in the plasma esomeprazole concentration when administering therapy "as necessary", 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 Helicobacter pylori the possibility of drug interactions for all components of triple therapy should be taken into account. Clarithromycin is a potent inhibitor CYP3A4, therefore, in the appointment of eradication therapy to patients receiving other drugs metabolized with participation CYP3A4 (eg, cisapride), possible contraindications and interactions of clarithromycin with these drugs must be considered.

Nexium tablets contain sucrose, which is why they are contraindicated in patients with hereditary intolerance to fructose, glucose-galactose malabsorption or sugar-isomaltase deficiency.

Effect on the ability to drive transp. cf. and fur:

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

Form release / dosage:Tablets coated with a coating, 20 mg and 40 mg.

Packaging:

For 7 tablets in aluminum blisters, 1, 2 or 4 blisters with instructions for use in a cardboard box with the control of the first opening.

When packing Corden Pharma GmbH, Germany: 7 tablets in aluminum blisters, 1, 2 or 4 blisters per cardboard pack with instructions for use.

When packing OOO AstraZeneca Industries, Russia:

For 7 tablets in aluminum blisters, 2 or 4 blisters with instructions for use in a cardboard box with the control of the first opening.

Storage conditions:

At temperatures not higher than 25 ° C, in the original packaging, in places not accessible to children.

Shelf life:

3 of the year. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N013775 / 01

Date of registration:31.05.2007 / 16.03.2016

Expiration Date:Unlimited

The owner of the registration certificate:AstraZeneca ABAstraZeneca AB Sweden

Manufacturer: & nbsp

ASTRAZENECA, AB Sweden

Information update date: & nbsp17.06.2014

Illustrated instructions

Instructions

Nexium® (Nexium)