Nexium coated pills 40mg N14
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Active ingredients
Esomeprazole
Release form
Coated pills
Composition
1 tablet contains - gefitinib 250 mg. Excipients: lactose monohydrate - 163.5 mg, microcrystalline cellulose - 50 mg, croscarmellose sodium - 20 mg, povidone (K29-32) - 10 mg, sodium lauryl sulfate - 1.5 mg, magnesium stearate - 5 mg. The composition of the film shell: hypromellose - 7.65 mg, macrogol 300 - 1.5 mg, iron red oxide (E172) - 900 μg, iron yellow oxide (E172) - 900 μg, titanium dioxide (E171) - 500 μg.
Pharmacological effect
Nexium (esomeprazole) is a specific proton pump inhibitor of the parietal cells of the gastric mucosa. Is the S-isomeric form of omeprazole. Cumulates and transforms to the active state in the secretory tubules, where it suppresses the proton pump (enzyme H + K + -ATPase), thereby developing inhibition of the secretion of hydrochloric acid. The drug begins to act within 60 minutes after taking 20-40 mg of esomeprazole. Repeated use of 20 mg of esomeprazole after 24 hours 1 time per day is accompanied by a decrease in gastric secretion due to the action of pentagastrin, by 90% on about 5 days of administration. A dose of 40 mg is effective for the treatment of reflux esophagitis. It is used to treat ulcers of the mucous membrane of the stomach and duodenum, in combination with a suitable antibiotic, allows to achieve the best effect of Helicobacter pylori eradication (90% of cases). As a rule, with the complex treatment of a peptic ulcer after the end of antibiotics, there is no need to continue antisecretory monotherapy. Clinical studies have shown that when taking the drug, the content of gastrin in the blood increases in response to a decrease in the production of hydrochloric acid. The increase in the number of endocrine cells that produce histamine occurs due to an increase in the concentration of gastrin in the blood. In some cases, there was an increase in the frequency of occurrence of granular cysts of the gastric mucosa with prolonged use of antisecretory drugs. This phenomenon is regarded as physiological in response to inhibition of the production of hydrochloric acid. Cysts are always benign and transient (disappear after the end of treatment). Omeprazole is effective for preventing the formation of peptic ulcers with concomitant therapy with non-steroidal anti-inflammatory drugs (even cyclooxygenase inhibitors - 2 selective groups). Nexium is an acid-dependent drug, it is used in the form of coated granules, inside.Esomeprazole is rapidly absorbed, Cmax is reached in the blood plasma approximately 60-120 minutes after internal use. Bioavailability after taking a single dose of 40 mg - 64%, increases to 90% in the case of repeated use. At a dose of 20 mg, the absolute bioavailability is respectively 50%, 68%. Blood plasma proteins bind 97% of the active substance. With simultaneous intake of esomeprazole and food, the antisecretory effect does not change, however, absorption can be slowed down. Biometabolism of most esomeprazole occurs with the participation of the enzyme CYP 2С19, the rest of the enzyme isomer: CYP 3A4, all reactions occur with the participation of cytochrome P450. The half-life is approximately 70 minutes after a second dose of esomeprazole after 24 hours. Eliminated from the body by the kidneys completely in the interval between taking the drug, does not accumulate in the body when taken 1 time in 24 hours. A smaller part of esomeprazole is excreted in the feces. Metabolites of the drug do not affect the secretion of hydrochloric acid. Less than 1% of esomeprazole is eliminated unchanged by the kidneys. Esomeprazole metabolism does not change in the case of the elderly patient (71-80 years). Women have a higher AUC value than men (by 30%), the choice for the dose for male and female patients is not affected. A special group of patients are weak metabolisers - people whose metabolism is due only to the effect of CYP 3A4. In weak metabolizers, the AUC figures (average per day) are 100% higher than those with pronounced activity and isomers (extensive metabolisers) - CYP 2C19 enzyme. This does not affect the choice of dosage for both groups of people. Disorders of the metabolism of esomeprazole in patients with the presence of liver failure was not detected. The rate of biotransformation decreases only with pronounced disorders, which leads to an increase in AUC by 2 times. Due to this, it is recommended to use a dose of esomeprazole equal to 20 mg per day for such patients. No studies were conducted to identify the characteristics of the metabolism of esomeprazole in patients with renal insufficiency. Since the metabolites are not eliminated by the kidneys, the biotransformation disorders should not be expected. Studies have been conducted in adolescence - the effect and parameters of the maximum concentration of omeprazole in the blood plasma from the age of 12 are the same as in adult patients.
Pharmacokinetics
Absorption and distribution.Esomeprazole is unstable in an acidic environment, therefore, for oral use, pills containing the drug granules are used, the shell of which is resistant to the action of gastric juice. In vivo, only a small fraction of esomeprazole is converted to the R-isomer. The drug is rapidly absorbed: Cmax in plasma is achieved within 1–2 hours after administration. The absolute bioavailability of esomeprazole after a single dose of 40 mg is 64% and increases to 89% on the background of daily intake 1 time per day. For a dose of 20 mg of esomeprazole, these figures are 50 and 68%, respectively. Vss in healthy people is approximately 0.22 l / kg. Esomeprazole is 97% bound to plasma proteins. Eating slows down and reduces the absorption of esomeprazole in the stomach, but this does not have a significant effect on the effectiveness of inhibition of the secretion of hydrochloric acid. Metabolism and excretion. Esomeprazole undergoes metabolism involving the cytochrome P450 system. The main part is metabolized with the participation of the specific polymorphic isoenzyme CYP2C19, thus forming hydroxylated and desmethylated metabolites of esomeprazole. Metabolism of the remaining part is carried out by CYP3A4 isoenzyme; this forms a sulfose derivative of esomeprazole, which is the main metabolite, which is determined in plasma. The parameters below reflect mainly the nature of pharmacokinetics in patients with increased activity of the isoenzyme CYP2C19. Total Cl after a single dose of the drug is approximately 17 l / h, after repeated intake of 9 l / h. T1 / 2 - 1.3 hours with regular admission 1 time per day. AUC increases with repeated administration of esomeprazole. The dose-dependent increase in AUC upon repeated administration of esomeprazole is non-linear in nature, 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 CYP2C19 isoenzyme by esomeprazole and / or its sulfonic derivative. With daily intake 1 time per day, esomeprazole is completely eliminated from the blood plasma during the interval between doses and does not accumulate. The major 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 in the urine, the rest is excreted in the feces.Less than 1% of unchanged esomeprazole is found in the urine. Features of pharmacokinetics in some groups of patients. Patients with reduced activity of the isoenzyme CYP2C19. Approximately (2.9 ± 1.5)% of the population has decreased activity of the CYP2C19 isoenzyme. In such patients, the metabolism of esomeprazole is mainly carried out as a result of the action of CYP3A4. When systematically taking 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. Mean plasma Cmax values in patients with reduced isoenzyme activity are increased by approximately 60%. These features do not affect the dose and method of application of esomeprazole. Elderly age. In elderly patients (71–80 years), the metabolism of esomeprazole does not undergo significant changes. Floor. After a single dose of 40 mg of esomeprazole, the average value of AUC in women is 30% higher than that in men. With daily intake of the drug 1 time per day, differences in pharmacokinetics in men and women are not observed. These features do not affect the dose and method of application of esomeprazole. Liver failure. In patients with mild and moderate liver failure, the metabolism of esomeprazole may be disturbed. In patients with severe hepatic insufficiency, the metabolic rate is reduced, which leads to an increase in the value of AUC for esomeprazole by 2 times. Renal failure. The study of pharmacokinetics in patients with renal insufficiency was not conducted. Since not the esomeprazole itself but its metabolites are eliminated through the kidneys, it can be assumed that the metabolism of esomeprazole in patients with renal insufficiency does not change. Childhood. In children aged 12–18 years after repeated administration of 20 and 40 mg of esomeprazole, the value of AUC and Tmax in plasma was similar to the values of AUC and Tmax in adults.
Indications
• therapy of Zollinger-Ellison syndrome; • reflux esophagitis (both symptomatic therapy and anti-relapse treatment, as well as etiological therapy of the ulcerative form of reflux gastritis); • Helicobacter pylori eradication - in combination treatment with antibacterial drugs for gastric ulcer and duodenal ulcer; • preventive therapy of peptic ulcers when using NSAIDs, treatment of ulcers caused by nonsteroidal anti-inflammatory drugs.
Contraindications
hypersensitivity to esomeprazole, substituted benzimidazoles or other ingredients that make up the drug; hereditary fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency; concomitant use with atazanavir and nelfinavir; children's age up to 12 years (due to the lack of data on the efficacy and safety of the drug in this group of patients); children's age over 12 years (according to other indications, except gastroesophageal reflux disease).
Precautionary measures
Take with caution in case of severe renal insufficiency (experience of use is limited). In hepatic insufficiency, the maximum allowable dose of esomeprazole is 20 mg / day. Dosage adjustment is not required in patients with renal insufficiency; however, in case of marked impairment of renal function, Nexium should be used with caution. Effect on ability to drive a car and other mechanisms. Due to the fact that dizziness, blurred vision and drowsiness may occur during therapy with Nexium, care should be taken when driving vehicles and other mechanisms.
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. With the introduction of esomeprazole animals did not reveal any direct or indirect negative impact on the development of the embryo or fetus. The introduction of the racemic mixture of the drug also did not have any negative effects on animals during pregnancy, childbirth, as well as during postnatal development. It is necessary to appoint drug to pregnant women only in that case when the expected advantage for mother exceeds possible risk for a fruit. It is not known whether esomeprazole is excreted in breast milk; therefore, Nexium should not be administered during breastfeeding.
Dosage and administration
Inside The pill should be swallowed whole with a liquid; pills can not be chewed or crushed.For patients with difficulty swallowing, pills can be dissolved in half a glass of non-carbonated water. Do not use other liquids, because the protective shell of the microgranules may dissolve. When the tablet is dissolved, stir the water until the tablet disintegrates and drink a suspension of microgranules immediately or no later than within 30 minutes. Then fill the glass in half with water, stir the residue and drink. Do not chew or crush microgranules. For patients who cannot swallow, pills should be dissolved in non-carbonated water and administered via a nasogastric tube. It is important that the chosen syringe and probe are suitable for this procedure. Instructions on the preparation and administration of the drug through a nasogastric tube are provided in the subsection "Dosing the drug through a nasogastric tube".
Side effects
Below are the side effects that do not depend on the dosing regimen of the drug, noted during the use of Nexium, both in clinical studies and in post-marketing studies. The frequency of side effects is given in the form of the following gradation: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000). On the part of the skin and subcutaneous tissues Infrequently: dermatitis, pruritus, rash, urticaria; Seldom: alopecia, photosensitization; Very rare: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis. From the musculoskeletal and connective tissue Rarely: arthralgia, myalgia; Very rare: muscle weakness. Of the nervous system Often: headache; Infrequently: dizziness, paresthesias, drowsiness; Rarely: a violation of taste. Mental Disorders Infrequently: insomnia; Rarely: depression, agitation, confusion; Very rare: hallucinations, aggressive behavior. Of the gastrointestinal tract Often: abdominal pain, constipation, diarrhea, flatulence, nausea / vomiting; Infrequently: dry mouth; Rarely: stomatitis, gastrointestinal candidiasis; Very rare: microscopic colitis (confirmed histologically). On the part of the liver and biliary tract Infrequently: increased activity of "liver" enzymes; Rarely: hepatitis (with or without jaundice); Very rarely: liver failure, encephalopathy in patients with liver diseases.On the part of the genital organs and mammary gland. Very rarely: gynecomastia. From the side of blood and lymphatic system Rarely: leukopenia, thrombocytopenia; Very rare: agranulocytosis, pancytopenia. On the part of the immune system Rarely: hypersensitivity reactions (eg, fever, angioedema, anaphylactic reaction / anaphylactic shock). On the part of the respiratory system, organs of the chest and mediastinum Rarely: bronchospasm. On the part of the kidneys and urinary tract Very rare: interstitial nephritis. On the part of the organ of vision Rare: blurred vision. Metabolism and nutrition Infrequently: peripheral edema; Rarely: hyponatremia; Very rarely: hypomagnesemia; hypocalcemia due to severe hypomagnesemia, hypokalemia due to hypomagnesemia. General disorders Rarely: malaise, sweating.
Overdose
To date, extremely rare cases of deliberate overdose have been described. Oral administration of esomeprazole at a dose of 280 mg was accompanied by general weakness and symptoms of the gastrointestinal tract. A single dose of 80 mg Nexium did not cause any negative effects. The antidote 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 with other drugs
Effect of esomeprazole on the pharmacokinetics of other drugs. A decrease in the secretion of hydrochloric acid in the stomach during treatment with esomeprazole and other proton pump inhibitors may lead to a decrease or increase in the absorption of drugs, the absorption of which depends on the acidity of the medium. Like other drugs that reduce the acidity of gastric juice, treatment with esomeprazole can lead to a decrease in the absorption of ketoconazole, itraconazole and erlotinib, and an increase in the absorption of drugs such as digoxin. Joint administration of omeprazole in a dose of 20 mg once a day and digoxin increases the bioavailability of digoxin by 10% (the bioavailability of digoxin increased by up to 30% in two out of ten patients). Omeprazole has been shown to interact with certain antiretroviral drugs. The mechanisms and clinical significance of these interactions are not always known.Increasing the pH value during omeprazole therapy may affect the absorption of antiretroviral drugs. Interaction at the level of an isoenzyme CYP2C19 is also possible. With the joint use of omeprazole and some antiretroviral drugs, such as atazanavir and nelfinavir, during therapy with omeprazole, a decrease in their concentration in serum is noted. Therefore, their simultaneous use is not recommended. The combined use 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 (the 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 effects of omeprazole on the bioavailability of atazanavir. With simultaneous use of omeprazole and saquinavir, an increase in serum concentration of saquinavir was observed, when used 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 is not recommended. Esomeprazole inhibits CYP2C19 - the main isoenzyme involved in its metabolism. Accordingly, the combined use of esomeprazole with other drugs whose metabolism involves the CYP2C19 isoenzyme, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., can 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 the Nexium in the “as needed” mode. With the joint intake of 30 mg of esomeprazole and diazepam, which is a substrate of the CYP2C19 isoenzyme, a decrease in the clearance of diazepam by 45% is noted. 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 the concentration of phenytoin in plasma at the beginning of treatment with esomeprazole and with its cancellation. 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 change the coagulation time in patients who take 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. According to the research results, pharmacokinetic / pharmacodynamic interaction between clopidogrel (loading dose 300 mg and maintenance dose 75 mg / day) and esomeprazole (40 mg / day orally) is noted, which leads to a decrease in the active metabolite clopidogrel by an average of 40% and decrease 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. simultaneously with therapy with clopidogrel and acetylsalicylic acid (ACK), and in analyzing the clinical outcomes of large-scale randomized trials, no increase in the risk of cardiovascular complications was observed with the combined use of clopidogrel and proton pump inhibitors, including esomeprazole. The results of a number of observational studies are controversial and do not give a definite answer about the presence or absence of an increased risk of thromboembolic cardiovascular complications against the background of the combined use of clopidogrel and proton pump inhibitors. When clopidogrel was used in conjunction with a fixed combination of 20 mg of esomeprazole and 81 mg of ASK, the active metabolite of clopidogrel decreased by almost 40% compared to clopidogrel monotherapy, and the maximum levels of inhibition of ADP-induced platelet aggregation were the same ASC in a low dose. The use of omeprazole in a dose of 40 mg led to an increase in Cmax and AUC (the 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. Joint administration of cisapride with 40 mg of esomeprazole leads to an increase in the values of 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. The slight lengthening of the QT interval, which was observed with cisapride monotherapy, did not increase with the addition of Nexium (see the section "Special Instructions").With simultaneous use of esomeprazole and tacrolimus, an increase in serum tacrolimus concentration was noted. Some patients noted an increase in the concentration of methotrexate on 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 short-term co-administration of esomeprazole and naproxen or rofecoxib did not reveal any clinically significant pharmacokinetic interaction. The effect of drugs on the pharmacokinetics of esomeprazole. CYP2C19 and CYP3A4 isoenzymes are involved in the metabolism of esomeprazole. 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 the 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, dosage adjustment of esomeprazole is not required. Correction of the dose of esomeprazole may be required in patients with severely impaired liver function and with prolonged use. Drugs that induce CYP2C19 and CYP3A4 isoenzymes, such as rifampicin and Hypericum perforatum preparations, when used together with esomeprazole can lead to a decrease in plasma concentration of esomeprazole due to the acceleration of the metabolism of esomeprazole.
special instructions
If there are any alarming symptoms (for example, such as significant spontaneous weight loss, repeated vomiting, dysphagia, vomiting with blood or melena), and also in the presence of a stomach ulcer (or if a stomach ulcer is suspected), the presence of a malignant neoplasm should be excluded, since Nexium treatment can smooth symptoms and delay diagnosis. In rare cases, atrophic gastritis was detected by histological examination of biopsy specimens of the gastric mucosa in patients who took omeprazole for a long time.Patients taking the drug for a long period (especially more than a year) should be under the regular supervision of a physician. Patients taking Nexium “as needed” should be instructed to contact their physician when symptoms change. Taking into account fluctuations in the concentration of esomeprazole in plasma in the appointment of therapy "as needed", you should consider the interaction of the drug with other drugs (see the section "Interaction with other drugs and other types of drug interactions"). In 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 metabolized with CYP3A4 (for example, cisapride), it is necessary to take into account possible contraindications and interactions of clarithromycin with these drugs. Nexium pills contain sucrose, so they are contraindicated in patients with hereditary fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase deficiency. According to the research results, pharmacokinetic / pharmacodynamic interaction between clopidogrel (loading dose 300 mg and maintenance dose 75 mg / day) and esomeprazole (40 mg / day orally) is noted, which leads to a decrease in the active metabolite of clopidogrel by an average of 40% inhibition of ADP-induced platelet aggregation by an average of 14%. Therefore, the simultaneous use of esomeprazole and clopidogrel should be avoided (see the section "Interaction with other drugs 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 in other similar studies there has been no 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 against osteoporosis with the use of proton pump inhibitors was not confirmed.Although the causal relationship between the use of omeprazole / esomeprazole and fractures against osteoporosis has not been established, patients at risk of developing osteoporosis or fractures against its background should be under appropriate clinical supervision. Impact on the ability to drive vehicles and control mechanisms Due to the fact that during therapy with the drug Nexium dizziness, blurred vision and drowsiness may be observed, care should be taken when driving vehicles and other mechanisms.