Nexium (Pills, coated)

Active material: Esomeprazole
When ATH: A02BC05
CCF: Inhibitor N⁺-K⁺-ATPase
ICD-10 codes (testimony): E16.8, K21, K21.0, K25, K26, K27
When CSF: 11.01.03
Manufacturer: ASTRAZENECA AB (Sweden)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Pills, coated light pink, oblong, lenticular, Engraved “20 mg” on one side and “A/EN” as a fraction – another.

Excipients: glycerol monostearate 40-55, giproloza, gipromelloza, iron oxide red, iron oxide yellow, magnesium stearate, Copolymer of methacrylic and ètakrilovoj acid (1:1), microcrystalline cellulose, paraffin, synthetic, macrogol, polysorbate 80, krospovydon, sodium fumarate, sucrose spherical granules, Titanium dioxide, talc, triэtiltsitrat.

7 PC. – blisters (1) – packs cardboard.
7 PC. – blisters (2) – packs cardboard.
7 PC. – blisters (4) – packs cardboard.

Pills, coated Pink colour, oblong, lenticular, Engraved “40 mg” on one side and “A/EI” as a fraction – another.

Excipients: glycerol monostearate 40-55, giproloza, gipromelloza, iron oxide red, magnesium stearate, Copolymer of methacrylic and ètakrilovoj acid (1:1), microcrystalline cellulose, paraffin, synthetic, macrogol, polysorbate 80, krospovydon, sodium fumarate, sucrose spherical granules, Titanium dioxide, talc, triэtiltsitrat.

7 PC. – blisters (1) – packs cardboard.
7 PC. – blisters (2) – packs cardboard.
7 PC. – blisters (4) – packs cardboard.

Pharmacological action

Inhibitor N⁺-K⁺-ATPase. The active substance of the drug Nexium^® – esomeprazole – is the S-isomer of omeprazole, decreases the secretion of hydrochloric acid in the stomach by a specific Proton pump inhibition in parietal cells. S- and R-isomer of omeprazole have similar pharmacodynamic activity.

Mechanism of action

Esomeprazole is a weak base, It accumulates and passes into the active form in the acidic environment of the secretory canaliculi of the parietal cells of the gastric mucosa, where ingibiruet Proton pump – фермент H⁺-K⁺-ATF canine. Esomeprazole inhibits both basal, and stimulated gastric secretion.

Effect on gastric acid secretion

The drug develops over 1 hours after the intake of the dose 20 mg or 40 mg. Daily admission medication for 5 days 20 mg 1 times/day average maximum concentration of acid in the gastric contents after stimulation pentagastrinom dropping 90% (When measuring the concentration of acid through the 6-7 hours after the dose on the 5th day of therapy).

In patients with gastroesophageal reflux disease and the presence of clinical symptoms through 5 days daily admission Neksiuma^® oral dose 20 mg or 40 mg pH was higher in the stomach 4 within an average of 13 and 17 hr from 24 no. Against the backdrop of the admission drug dose 20 mg/day intragastric pH value above 4 maintained during 8, 12 and 16 h is reached 76%, 54% and 24% of patients, respectively. To 40 mg èzomeprazola the ratio is 97%, 92% and 56% respectively.

Correlation between secretion of acid and the concentration of the drug in plasma (We were used to estimate the concentration of the parameter AUC).

Therapeutic effect, achieved as a result of inhibition of acid secretion

When taking Neksiuma^® dose 40 mg/day cure reflux-esophagitis occurs in approximately 78% patients through 4 weeks of therapy and 93% – through 8 weeks of therapy.

Treatment Neksiumom^® dose 20 mg 2 times/day in combination with appropriate antibiotics for one week leads to successful eradication of Helicobacter pylori in approximately 90% patients.

Patients with uncomplicated ulcers after a week èradikacionnogo course does not require subsequent alone antisekretornymi drugs for healing sores and symptoms.

Other effects, associated with the inhibition of acid secretion

During treatment antisecretory gastrin levels in plasma increased as a result of reduction of acid secretion.

Patients, for a long time treated with esomeprazole, There has been an increase in the number of ènterohromaffinopodobnyh cells, probably, associated with higher levels of gastrin plasma.

Patients, perpetrators of antisecretory drugs for a long time, often marked the formation of cysts in the glandular stomach. This phenomenon is due to physiological changes as a result of inhibition of acid secretion. Cysts are benign and are reversible.

During the two conducted comparative studies with Nexium ranitidine^® showed better efficiency in relation to healing chronic ulcers in patients, treated with anti-inflammatory therapy nesteroidnuû, including selective COX-2 inhibitors.

In two studies to assess the effectiveness of Nexium^® showed better efficiency in prevention of peptic ulcers in patients (age group over 60 years and/or with a history of peptic ulcer), treated with anti-inflammatory therapy nesteroidnuû, including selective inhibitors of Cox-2.

Pharmacokinetics

Absorption and distribution

Esomeprazole is unstable in acidic Wednesday, so for the reception inside use pills, containing pellets of the drug, coated, resistant to the action of the gastric juice.

After taking the drug inside esomeprazole is rapidly absorbed from the digestive tract; C_max achieved through 1-2 no. Absolute bioavailability after a single dose in 40 mg of 64% and increases to 89% against the backdrop of daily reception 1 time / day. For dose 20 mg èzomeprazola these figures are 50% and 68%, respectively. In equilibrium (V)_d healthy people is approximately 0.22 l / kg. Plasma protein binding – 97%. Simultaneous eating slows down and reduces absorption of èzomeprazola in the stomach.

Metabolism and excretion

In vivo only a fraction of èzomeprazola turns into the R-isomer. Esomeprazole biotransformiroetsa fully involving cytochrome P₄₅₀ (CYP). The main part is metabolized with the participation of specific polymorphic isoform CYP2C19, thus formed hydroxy- and the demethylated metabolites èzomeprazola. The metabolism of the remaining part is carried out another specific isoform CYP3A4, with the formation of esomeprazole sulfoderivatives, which is the major metabolite, determined in plasma.

Options, below, reflect, primarily, nature of pharmacokinetics in patients with active enzyme CYP2C19 (Patients with rapid metabolism).

Total clearance is approximately 17 l / h after a single dosing and 9 l / – after multiple dose. T_1/2 is 1.3 h, with regular admission 1 time / day. AUC dozozawisimo increases when taken regularly and is expressed in a nonlinear dependence of dose and AUC. Such temporary and radiation is a consequence of the reduced dependence of metabolism at èzomeprazola “first pass” through the liver, as well as lower systemic clearance, probably caused by the fact, that esomeprazole and/or its sul′fosoderžaŝij metabolite inhibit CYP2C19 enzyme. Daily admission 1 times/SUT esomeprazole completely withdrawn from blood plasma during the break between meals and not koumouliruet.

None of the major metabolites of èzomeprazola does not affect the secretion of stomach acid. When taking the drug inside to 80% dose is excreted as metabolites in urine, the remainder is excreted in feces. The urine is detected less 1% unchanged esomeprazole.

Pharmacokinetics in special clinical situations

Approximately 1-2% population reduced CYP2C19 isoenzyme (patients with slow metabolism). Èzomeprazola metabolism such patients is mainly as a result of the CYP3A4. The systematic admission 40 mg esomeprazole 1 times/day AUC on 100% exceeds the value of this parameter in patients with active enzyme CYP2C19 (Patients with rapid metabolism). Average value of C_max in patients with slow metabolisms increased by approximately 60%.

Elderly patients (71-80 years) metabolism of èzomeprazola does not undergo significant changes.

After a single dose 40 mg esomeprazole the mean AUC of women on 30% exceeds such men. With regular daily admission of drug 1 times/day differences in pharmacokinetics in patients of both sexes is not observed (These differences do not affect the dosage of the drug).

In patients with mild to moderate hepatic insufficiency èzomeprazola metabolism may be disrupted. In patients with severe hepatic insufficiency, metabolic rate reduced, which leads to an increase in AUC 2 times for èzomeprazola.

Study of pharmacokinetics in patients with renal insufficiency has not been. Since the removal is carried out through the kidneys not of esomeprazole, and its metabolites, it can be assumed, that the metabolism of èzomeprazola in patients with renal insufficiency is not changed.

In children 12-18 years after repeated admission èzomeprazola dose 20 mg 40 mg AUC value and time to reach the maximum concentration in plasma was similar to values in adults.

Testimony

Gastroesophageal reflux disease:

— treatment of erosive reflux esophagitis;

— prolonged maintenance therapy in patients after healing of erosive reflux esophagitis for relapse prevention;

-symptomatic therapy of gastroesophageal reflux disease.

Peptic ulcer and duodenal (in a combination therapy):

-treatment of duodenal ulcer, associated with Helicobacter pylori;

-Prevention of the recurrence of peptic ulcers associated with Helicobacter pylori.

Patients, long-term taking NSAIDS:

-the healing of gastric ulcers, associated with taking NSAIDS;

-Prevention of ulcers stomach and duodenal ulcers, associated with taking NSAIDS in patients, at risk.

Zollinger-Ellison syndrome or other conditions, characterized by pathological hypersecretion, (incl. idiopathic hypersecretion).

Dosage regimen

At gastroesophageal reflux disease adults and children over 12 years Nexium^® to appoint treatment of erosive reflux esophagitis single dose 40 mg 1 times / day for 4 weeks. Optional 4-week course of therapy recommended in those cases, When the first course is not healing esophagitis or symptoms persist. To long-term maintenance therapy of patients with healed esophagitis èrozivnym to prevent the recurrence of the preparation appoint 20 mg 1 time / day. To symptomatic therapy of gastroesophageal reflux disease without esophagitis the drug is prescribed in a dose 20 mg 1 time / day. If the 4 weeks of treatment, the symptoms do not disappear, should conduct an additional examination of the patient. After the symptoms, you can go to the mode of administration of the drug “of necessity”, ie. take Nexium^® by 20 mg 1 times/day if you experience symptoms until their withdrawal. Patient, taking NSAIDS and risk of the development of gastric ulcer or duodenal ulcer, We do not recommend treatment if necessary, mode.

Adults at gastric ulcer and duodenal ulcer in a combination therapy for eradication of Helicobacter pylori, as well as for the treatment of duodenal ulcer, associated with Helicobacter pylori and peptic ulcers to prevent recurrence, associated with Helicobacter pylori in patients with peptic ulcer Nexium^® administered in one dose 20 mg, amoksiцillin – 1 g, clarithromycin – 500 mg. All products are accepted 2 times / day for 7 days.

Pacientam, long-term receiving NSAIDS, to the healing of gastric ulcers, associated with taking NSAIDs, Nexium^® administered at a dose of 20 mg or 40 mg 1 time / day. The duration of treatment is 4-8 weeks.

To Prevention of stomach ulcers and duodenal ulcers, associated with taking NSAIDs, Nexium^® administered at a dose of 20 mg or 40 mg 1 time / day.

At states, characterized by pathological hypersecretion, incl. syndrome Zollinger-Ellison syndrome and idiopathic gipersecretii Nexium^® administered in an initial dose of 40 mg 2 times / day. In the future, the dose is adjusted individually, duration of treatment is determined by the clinical picture of the disease. There is experience with the drug in doses up to 120 mg 2 times / day.

In appointing the drug patients with impaired renal function dose adjustment is not required. Be wary drug in patients with renal insufficiency severe due to limited clinical experience of its use in this category of patients.

In appointing Neksiuma^® patients liver failure mild or moderate dose adjustment is not required. Patients with severe hepatic insufficiency applied dose should not exceed 20 mg / day.

Elderly patients correction mode is not required.

The tablets should be swallowed whole, with some liquid. Canines pills or kibble. Patients with difficulty swallowing can dissolve the tablet in half a glass of carbonated water (do not use any other liquid, tk. protective shell granules can dissolve), stir until raspadeniâ pills and drink suspended microgranules immediately or within 30 m. Then you should again fill the glass halfway with water, stir and drink. You should not chew or crush micro.

Patient, who can't swallow, the tablets should be dissolved in carbonated water and enter via the nasogastric route because. Important, to the selected syringe and probe have been thoroughly tested.

The introduction of the drug via the nasogastric route because

1. Place the Tablet into the syringe and fill syringe 25 ml of water and approximately 5 ml air. Some probes may require medication in breeding 50 ml of drinking water, to prevent clogging probe pellets tablets.

2. Immediately shake the syringe within approximately 2 minutes for dissolving tablets.

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

4. Enter the syringe tip in probe, hold it upwards.

5. Shake the syringe and turn it over the tip down. Immediately enter 5-10 ml of dissolved drug probe. After the introduction of the return the syringe and shake the previous provision (the syringe must be maintained to avoid clogging up the tip of the handpiece).

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

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

Side effect

The following side effects do not depend on the dose.

Often (>1/100, <1/10): headache, abdominal pain, diarrhea, flatulence, nausea, vomiting, constipation.

Less often (>1/1000, <1/100): dermatitis, itch, hives, rash, dizziness, dry mouth, insomnia, paraesthesia, drowsiness, increase in liver enzymes, peripheral edema.

Rarely (>1/10000, <1/1000): leukopenia, thrombocytopenia, allergic reactions: fever, angioedema, anaphylactoid reactions; excitation, depression, confusion, changes in taste, giponatriemiya, blurred vision, bronchospasm, stomatitis, gastrointestinal candidiasis, hepatitis C (or without) jaundice, photosensitivity, alopecia, arthralgia, myalgia, malaise.

Rarely (<1/10000): agranulocytosis, pancytopenia, hallucinations (mainly the weakened patients), violent behavior, hepatic failure, hepatic encephalopathy, erythema multiforme exudative, Stevens-Johnson syndrome, toxic epidermal necrolysis, muscular weakness, interstitial nephritis, gynecomastia.

Contraindications

-hereditary fructose intolerance;

-glucose-galaktoznaâ malabsorption;

— saharazo-izomal′taznaâ failure;

- Children up to age 12 years (in the absence of data on the effectiveness and safety of drugs in this group of patients);

— children's age 12 years for other indications, except for gastroesophageal reflux disease;

- Hypersensitivity to esomeprazole, substituted benzimidazolam or other components of the drug.

FROM caution should designate product in severe renal insufficiency (limited experience in the application). Esomeprazole (like other Proton pump inhibitors) should not be applied in conjunction with atazanavir.

Pregnancy and lactation

Currently, there is not enough data on the use of Neksiuma^® Pregnancy. Use of the drug during this period is possible only in case of, if the expected benefit to the mother outweighs the potential risk to the fetus.

The results of epidemiological studies of omeprazole, represents the razemicescuu mixture, fetotoksičeskogo showed a lack of action or violations of fetal development.

IN experimental studies on animals not revealed any adverse effects of èzomeprazola on the development of embryo or fetus. The introduction of the racemic drug also does not have any negative impact on the course of pregnancy, childbirth and postpartum period in animals.

It is currently unknown, whether allocated esomeprazole with breast milk, therefore, should not be given Nexium^® during breastfeeding.

Cautions

In the presence of any alarm symptoms (incl. a large spontaneous weight loss, repeated vomiting, dysphagia, vomiting with admixture of blood or melena), and in the presence of gastric ulcers (or suspected stomach ulcer) should rule out the presence of cancer, as treatment Nexium^® It can lead to a smoothing of the symptoms and delay diagnosis.

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

Patients, located on the mode of therapy “of necessity”, should be instructed on the need to contact your doctor if you change the nature of the symptoms. Taking into account the fluctuations in plasma èzomeprazola concentration in appointing the drug therapy mode “of necessity”, should take into account the interaction of the drug with other drugs.

In appointing Neksiuma^® for Helicobacter pylori must take into account the possibility of drug interactions for all components of the triple therapy. Clarithromycin is a potent inhibitor of CYP3A4, Therefore, when the appointment of eradication therapy patients, receiving other drugs, metaboliziruûŝiesâ with the participation of CYP3A4 (eg, cisapride), It is necessary to take into account the possible contraindications and interaction with these medicines clarithromycin.

Tablets contain sucrose, therefore, should not be given Nexium^® patients with hereditary fructose intolerance, glucose-galaktoznoj malabsorbziei or saharozo-izomal′taznoj failure.

Effects on ability to drive vehicles and management mechanisms

We found no influence on the ability to drive vehicles and management mechanisms.

Overdose

Currently describes the extremely rare cases of intentional overdose.

Symptoms: When taken in the dose of èzomeprazola 280 mg inside have experienced weakness and manifestations of the digestive tract. Single admission Neksiuma^® dose 80 mg inside have not caused any negative effects.

Treatment: When simptomaticescuu and supportive therapy. Spetsificheskiy antidote unknown. Dialysis maloeffyektivyen, tk. esomeprazole is associated with plasma proteins.

Drug Interactions

Influence of èzomeprazola on farmakokinetiku other medications

Reduce gastric acidity esomeprazole treatment may lead to a change in the absorption of drugs, absorption depends on acidity Wednesday.

Esomeprazole, both antacids and other medications, reduce the secretion of acid in the stomach, may reduce absorption of ketoconazole and itraconazole.

Joint appointment omeprazole dose 40 mg 1 times/day and atazanavir 300 mg/ritonavir 100 mg resulted in a significant decrease in AUC values, as well as the maximum and minimum concentration of atazanavir in healthy volunteers. Increasing the dose to atazanavir 400 mg is not offsetting the influence of omeprazole on the concentration of atazanavir. Therefore, you should not assign esomeprazole in conjunction with atazanavir.

Эзомепразол ингибирует CYP2C19 – the main enzyme, involved in its metabolism. Respectively, combined use of èzomeprazola with other drugs, in the metabolism of which involved CYP2C19 (eg, diazepam, citalopram, imipramine, clomipramine, phenytoin), can lead to increased concentrations of these drugs in plasma, what, in turn, will lead to the need to reduce the dose. This phenomenon is especially pronounced when using Neksiuma^® therapy mode “of necessity”. When 30 mg èzomeprazola and diazepam on 45% reduced clearance of enzyme-substrate complex (CYP2C19-diazepam).

Minimum concentration fenitoina plasma patients with epilepsy increased on 13% When combined it with a dose of esomeprazole 40 mg. It is therefore recommended to control concentration fenitoina plasma at the beginning of treatment, and with the abolition of esomeprazole.

Joint reception of warfarin with the dose of esomeprazole 40 mg does not change the time of coagulation in patients, long-term taking warfarin. However, it was reported on several cases of clinically significant increase index INR in joint application of warfarin and èzomeprazola. Therefore we recommend monitoring patients at the beginning and at the end of the joint application of these drugs.

Joint reception with cisapride dose of esomeprazole 40 mg leads to increased values farmakokineticeskih parameters cisapride: AUC – on 32% and T_1/2 – on 31%, However, concentrations of cisapride in plasma have not changed significantly. Slight elongation QT interval, that seen during monotherapy cizapridom, When adding Neksiuma^® not increased.

Nexium^® does not cause any clinically significant changes in the pharmacokinetics of amoxicillin and hinidina.

Study on evaluation of combined use of èzomeprazola and naproksena or rofekoksiba did not reveal any clinically significant pharmacokinetic interaction.

The impact of drugs on farmakokinetiku èzomeprazola

Èzomeprazola participate in the metabolism of CYP2C19 and CYP3A4. Combined use of èzomeprazola with clarithromycin (500 mg 2 times / day), which inhibits CYP3A4, leads to increased exposure AUC èzomeprazola in 2 times. Combined use of èzomeprazola and combined inhibitor CYP3A4 and CYP2C19, eg, vorikonazola, can lead to a more than 2-fold increase in AUC values for èzomeprazola. In such cases, do not require dose adjustment èzomeprazola.

Conditions of supply of pharmacies

The drug is released under the prescription.

Conditions and terms

Tablets should be stored in a place inaccessible to children at a temperature of no higher than 30° c in its original packaging. Shelf life – 3 year. Do not use beyond the expiration date.