Nexium, pellets and 10 mg 28 pcs

Pharmacotherapeutic group: A gastric gland secretion reducing agent – proton pump inhibitor

ATX code: A02BC05

Pharmacological Properties

.Pharmacodynamics

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

Mechanism of action

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

Influence on gastric hydrochloric acid secretion

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

In patients with gastroesophageal reflux disease (GERD) and the presence of clinical symptoms after 5 days of daily oral administration of esomeprazole at a dose of 20 mg or 40 mg, intragastric pH values above 4 were maintained for an average of 13 and 17 hours out of 24 hours. On background administration of esomeprazole at a dose of 20 mg per day, intragastric pH values above 4 were 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.

The correlation between the drug concentration in plasma and inhibition of hydrochloric acid secretion was found (to estimate the concentration we used the parameter AUC (area under the curve “concentration – time”).

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

The healing of reflux esophagitis occurred in approximately 78% of patients after 4 weeks of therapy and in 93% after 8 weeks of therapy with Nexium® at a dose of 40 mg.

The treatment with Nexium® in a dose of 20 mg twice daily 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 disease after a one-week course of eradication do not require subsequent monotherapy with drugs that reduce gastric gland secretion to heal the ulcer and relieve symptoms.

Nexium® has been shown to be effective in peptic ulcer bleeding confirmed by endoscopic examination.

Application in GERD in children (ages 1-11 years)

Healing of erosive esophagitis confirmed by endoscopic study data was observed in 93.3% of patients aged 1-11 years after 8 weeks of therapy with Nexium®. Patients with body weight less than 20 kg took Nexium® in a daily dose of 5 mg or 10 mg, and patients with body weight over 20 kg – in a daily dose of 10 mg or 20 mg.

Other effects related to inhibition of hydrochloric acid secretion

During treatment with drugs that decrease gastric gland secretion, plasma gastrin concentration increases as a result of decreased hydrochloric acid secretion. Because of the decrease in hydrochloric acid secretion, chromogranin A (CgA) concentrations are increased. Increased CgA concentrations may affect the results of neuroendocrine tumor screenings. To prevent this effect, therapy with proton pump inhibitors should be stopped 5-14 days before CgA concentration testing. If the CgA concentration has not returned to normal during this time, the study should be repeated.

In children and adult patients treated with esomeprazole for a long time, an increase in enterochromaffin-like cells has been observed, probably due to an increase in plasma gastrin concentration. This phenomenon has no clinical significance.

In patients taking drugs that reduce gastric gland secretion over a long period of time, formation of glandular cysts in the stomach is more often observed. These phenomena are due to physiological changes resulting from a pronounced inhibition of hydrochloric acid secretion. The cysts are benign and undergo reverse development.

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

Nexium® showed better efficacy compared to ranitidine for gastric ulcer healing in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors.

The 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, so enteric-coated pellets 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: maximum plasma concentration is reached 1-2 hours after administration. Absolute bioavailability of esomeprazole after a single dose of 40 mg is 64% and increases to 89% after daily dosing. For the 20 mg dose of esomeprazole these figures are 50% and 68%, respectively. The volume of distribution at equilibrium concentration in healthy subjects is approximately 0.22 l/kg body weight. Esomeprazole is 97% bound to plasma proteins.

Eating slows down and reduces absorption of esomeprazole in the stomach, but this has no significant effect on the effectiveness of inhibiting hydrochloric acid secretion.

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, with the formation of hydroxylated and desmethylated metabolites of esomeprazole. The remainder is metabolized by the CYP3A4 isoenzyme; this produces esomeprazole sulfo-derivative, which is the main plasma-detectable metabolite.

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

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 with systemic administration once daily. The area under the curve “concentration

times” (AUC) increases with repeated administration of esomeprazole. The dose-dependent increase in AUC with repeated administration of esomeprazole is nonlinear, which is a consequence of a decrease in metabolism during “first passage” through the liver and a decrease in systemic clearance, probably caused by inhibition of the CYP2C19 isoenzyme by esomeprazole and/or its sulfo-derivatives. When administered once daily, esomeprazole is completely eliminated from the blood plasma between doses and does not cumulate.

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

Peculiarities of pharmacokinetics in some groups of patients. In approximately 2.9±1.5% of the population the activity of CYP2C19 isoenzyme is reduced. In these patients the metabolism of esomeprazole is mainly due to the action of CYP3A4. When systemically administered with 40 mg of esomeprazole once daily, the average AUC is 100% higher than that of patients with increased CYP2C19 isoenzyme activity. Mean values of maximum plasma concentrations in patients with decreased isoenzyme activity are increased by approximately 60%. These characteristics do not affect the dose and route of administration of esomeprazole.

The metabolism of esomeprazole is not significantly altered in elderly patients (71-80 years).

After a single dose of 40 mg of esomeprazole, the average AUC in women is 30% higher than in men. There are no differences in pharmacokinetics in men and women when taking the drug once daily. These characteristics do not affect the dose and route of administration of esomeprazole.

The metabolism of esomeprazole may be impaired in patients with mild to moderate hepatic impairment. In patients with severe hepatic insufficiency the metabolic rate is reduced, resulting in a 2-fold increase in the AUC value for esomeprazole. For patients with severe hepatic impairment, the maximum daily dose of 20 mg should not be exceeded. No cumulation of esomeprazole and its major metabolites has been observed when administered once daily.

There have been no studies of pharmacokinetics in patients with renal insufficiency. Since the kidneys do not excrete esomeprazole itself, but its metabolites, it can be assumed that the metabolism of esomeprazole in patients with renal impairment is not altered.

In children aged 12-18 years after repeated administration of 20 mg and 40 mg of esomeprazole, the AUC and time to peak plasma concentration (TCmax) were similar to the AUC and TCmax values 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 receiving 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 receiving 20 mg of esomeprazole.

Indications

– symptomatic treatment of GERD

– treatment of duodenal ulcer associated with Helicobacter pylori

– prevention of recurrence of peptic ulcer associated with Helicobacter pylori

Active ingredient

Composition

How to take, the dosage

Nexium® in the dosage form of enteric-coated pellets and granules for oral suspension is intended primarily for pediatric patients and persons with difficulty in swallowing.

Ingestion. To take 10 mg of Nexium® , pour the contents of one sachet in a glass with 15 ml of water. To take 20 mg of Nexium®, pour the contents of 2 sachets into a glass containing 30 ml of water. To take 40 mg of Nexium®, pour the contents of 4 sachets into a glass containing 60 ml of water. Stir the glass and wait for 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 15 ml of water should be added to the glass again, stirred and taken orally. Carbonated water should not be used. Pellets and pellets should not be chewed or crushed.

The suspension may be administered through a nasogastric tube. For instructions on preparation and administration through the nasogastric tube, see “Administration through the nasogastric tube”.

Children 1-11 years of age with body weight ≥10 kg .GERD

Treatment of erosive reflux esophagitis: For patients with a body weight greater than 10 kg but less than 20 kg, 10 mg once daily for 8 weeks. For patients with a body weight of 20 kg or more – 10 mg or 20 mg once daily for 8 weeks. Symptomatic treatment of GERD: 10 mg once daily for 8 weeks.

The use of esomeprazole in doses greater than 1 mg/kg/day has not been studied.

Children from 4 years

In combination therapy

Treatment of duodenal ulcer associated with Helicobacter pylori

. When selecting combination therapy, official national, regional, and local recommendations regarding bacterial resistance, duration of therapy (most often 7 days, sometimes up to 14 days), and appropriate use of antibacterial agents should be considered.

The treatment should be conducted under the supervision of a physician. Dosing recommendations:

Body weight

Dosing regimen

< 30 kg

Nexium® 10 mg twice daily for 1 week in combination with amoxicillin and clarithromycin. Clarithromycin and amoxicillin are administered in a dosing regimen according to the instructions for use

clarithromycin and amoxicillin.

30 – 40 kg

Nexium® 20 mg twice daily for 1 week in

combination with amoxicillin and clarithromycin. Clarithromycin and amoxicillin are prescribed in

dosing according to the instructions for use

clarithromycin and amoxicillin.

> 40 kg

Nexium® 20 mg twice daily for 1 week in combination with amoxicillin and clarithromycin. Clarithromycin and amoxicillin are administered in a dosing regimen according to the instructions for use

clarithromycin and amoxicillin.

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

An additional 4-week course of treatment is recommended in cases where esophagitis does not heal or symptoms persist after the first course.

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

Symptomatic treatment of GERD: 20 mg once daily in patients without esophagitis. If after 4 weeks of treatment the symptoms do not disappear, further examination of the patient should be carried out. After elimination of symptoms, it is possible to switch to the drug regimen “as needed”, i.e. to take Nexium® 20 mg once daily when symptoms recur. For patients taking NSAIDs who are at risk of gastric or duodenal ulcer, treatment on an “as needed” regimen is not recommended.

Adults

Gastric and duodenal ulcer

In combination therapy for eradication of Helicobacter pylori:

Nexium® 40 mg once daily for 4 weeks after completion of intravenous therapy with gastric gland-lowering drugs.

Conditions associated with pathological hypersecretion of gastric glands, including Zollinger-Ellison syndrome and idiopathic hypersecretion: The recommended initial dose is Nexium® 40 mg twice daily. Subsequently, the dose is adjusted individually; the duration of treatment is determined by the clinical picture of the disease. There is experience of using the drug in doses up to 120 mg twice daily.

In children under 1 year of age or with body weight less than 10 kg: Because of absence of data about efficacy and safety, Nexium® should not be used in children under 1 year of age or with body weight less than 10 kg.

Renal failure: Dose adjustment of the drug is not required. However, experience in using Nexium® in patients with severe renal impairment is limited; therefore, caution should be exercised when prescribing the drug in these patients (see section “Pharmacokinetics”).

Hepatic impairment: In mild to moderate hepatic impairment, no dose adjustment is required. For patients with severe hepatic impairment, the maximum daily dose should not be exceeded

10 mg for patients aged 1-11 years and 20 mg for patients over 12 years.

Elderly patients: no dose adjustment is required.

The unused suspension should be destroyed.

Interaction

Effects of esomeprazole on the pharmacokinetics of other drugs. Decreased gastric hydrochloric acid secretion during treatment with esomeprazole and other proton pump inhibitors may lead to decreased or increased absorption of drugs whose absorption depends on the acidity of the environment. Like other drugs that reduce gastric acidity, treatment with esomeprazole may lead to decreased absorption of ketoconazole, itraconazole and erlotinib, and increased absorption of drugs such as digoxin. Co-administration of omeprazole in dose of 20 mg once daily and digoxin increases digoxin bioavailability by 10% (digoxin bioavailability was 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 antiretrovirals. There may also be an interaction at the level of CYP2C19 isoenzyme. When coadministration of omeprazole and some antiretroviral drugs such as atazanavir and nelfinavir during therapy with omeprazole, a decrease in their serum concentrations is noted. Therefore, their concomitant use is not recommended. The co-administration of atazanavir (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg in healthy volunteers significantly decreased the bioavailability of atazanavir (the area under the “concentration-time curve”, the maximum (Cmax) and minimum (Cmin) concentrations were reduced by approximately 75%). Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir bioavailability.

Concomitant use of omeprazole and saquinavir resulted in increased serum concentrations of saquinavir; when used with some other antiretrovirals their concentrations were unchanged. 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, co-administration of esomeprazole with other drugs whose metabolism involves the CYP2C19 isoenzyme, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., may lead to increased plasma concentrations of these drugs, which in turn may require dose reduction. This interaction is particularly important to keep in mind when using Nexium® in the “as needed” regimen. When co-administration of esomeprazole 30 mg and diazepam, which is a substrate of CYP2C19 isoenzyme, there is a 45% decrease of diazepam clearance.

The use of esomeprazole at a dose of 40 mg resulted in a 13% increase in residual phenytoin concentrations in patients with epilepsy. Therefore, it is recommended to monitor plasma concentrations of phenytoin at the beginning of treatment with esomeprazole and at its withdrawal.

The use of omeprazole in dose of 40 mg once daily increased area under curve “concentration-time” and Cmax of voriconazole (substrate of CYP2C19 isoenzyme) by 15% and 41%, respectively.

The co-administration of warfarin with 40 mg of esomeprazole does not alter the coagulation time in patients taking long-term warfarin. However, several cases of clinically significant increase in INR (international normalized ratio) have been reported with co-administration of warfarin and esomeprazole. It is recommended to monitor INR at the beginning and at the end of coadministration of esomeprazole and warfarin or other coumarin derivatives.

In studies, pharmacokinetic/pharmacodynamic interactions between clopidogrel (loading dose 300 mg and maintenance dose 75 mg/day) and esomeprazole (40 mg/day) have been reported. orally), which results in an average 40% decrease in exposure to the active metabolite clopidogrel and an average 14% decrease in maximum inhibition of ADP-induced platelet aggregation.

The clinical significance of this interaction is unclear. In a prospective study in patients receiving placebo or omeprazole at a dose of 20 mg/day concomitantly with clopidogrel and acetylsalicylic acid (ASA) therapy and in an analysis of clinical outcomes of large randomized trials, no increased risk of cardiovascular complications was shown when clopidogrel and proton pump inhibitors including esomeprazole were used together.

The results of several observational studies are inconsistent and do not provide a definitive answer about the presence or absence of an increased risk of thromboembolic cardiovascular complications with clopidogrel and proton pump inhibitors.

When clopidogrel was coadministered with a fixed combination of 20 mg of esomeprazole and 81 mg of ASA, exposure to the active metabolite clopidogrel was reduced by nearly 40% compared with clopidogrel monotherapy, while maximum levels of inhibition of ADP-induced platelet aggregation were similar, which is likely due to the simultaneous administration of low-dose ASA.

Esomeprazole, like omeprazole, inhibits the CYP2C19 isoenzyme. Co-administration of cilostazol and 40 mg of omeprazole leads to an increase in pharmacokinetic parameters of cilostazol in healthy volunteers: Cmax and AUC by 18% and 26%, respectively. Similar parameters of one of the active metabolites of cilostazolum are increased by 29% and 69%, respectively.

Special Instructions

Synopsis

Contraindications

Side effects

The following are the dose-independent adverse reactions noted in clinical studies and post-marketing use of the drug.

The frequency of adverse reactions is given as the following gradation: Very common (≥1/10); common (≥1/100, < 1/10); infrequent (≥1/1000, < 1/100); rare (≥1/10000,

< 1/1000); very rare (< 1/10000).

Skin and subcutaneous tissue Infrequent: dermatitis, itching, rash, urticaria; Seldom: alopecia, photosensitization;

very rarely: multiform erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms (DRESS syndrome).

Skeletal, muscular and connective tissue Rarely: arthralgia, myalgia;

very rare: muscular weakness.

Nervous system Often: headache;

Infrequent: dizziness, paresthesias, drowsiness;

Rarely: disorder of taste.

Mental disorders Infrequent: insomnia;

Rarely: depression, agitation, confusion;

very rarely: hallucinations, aggressive behavior.

Gastrointestinal tract

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

Infrequent: dry mouth;

Rarely: stomatitis, gastrointestinal candidiasis;

Very frequently: microscopic colitis.

Hepatic and biliary tract disorders

Infrequent: increased activity of “liver” enzymes;

Rarely: hepatitis (with or without jaundice);

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

Gender and mammary gland Very rare: gynecomastia.

Blood and lymphatic system Rarely: leukopenia, thrombocytopenia;

very rare: agranulocytosis, pancytopenia.

An immune system side

Rarely: hypersensitivity reactions (e.g., fever, angioedema, anaphylactic reaction/anaphylactic shock).

Breathing system, chest and mediastinum Rarely: bronchospasm.

Kidney and urinary tract Very rare: interstitial nephritis.

Visual organ Rarely: blurred vision.

Metabolism and nutrition Infrequent: peripheral edema;

Rarely: hyponatremia;

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

General disorders

Rarely: malaise, sweating.

Overdose

Pregnancy use

Similarities