Nexium^® (Tablets, Lyophilisate, Pellets) Instructions for Use

ATC Code

A02BC05 (Esomeprazole)

Active Substance

Esomeprazole (Rec.INN registered by WHO)

Clinical-Pharmacological Group

H⁺-K⁺-ATPase inhibitor

Pharmacotherapeutic Group

Acid-related disorder treatment agents; antiulcer agents and agents for the treatment of gastroesophageal reflux disease (GERD); proton pump inhibitors

Pharmacological Action

H⁺-K⁺-ATPase inhibitor, the dextrorotatory isomer of omeprazole. It reduces the secretion of hydrochloric acid in the stomach by specifically inhibiting the proton pump in parietal cells.

Being a weak base and converting to the active form in the acidic environment of the secretory tubules of the gastric mucosa parietal cells, it is activated and inhibits the proton pump – the enzyme H⁺-K⁺-ATPase.

It inhibits both basal and stimulated secretion of hydrochloric acid. The effect occurs 1 hour after oral administration of 20 mg or 40 mg.

With daily use for 5 days at a dose of 20 mg once a day, the average maximum concentration of hydrochloric acid after stimulation with pentagastrin decreases by 90%.

Pharmacokinetics

After oral administration, Esomeprazole is rapidly absorbed. C_max in blood plasma is reached in 1-2 hours. The absolute bioavailability of esomeprazole after a single dose of 40 mg is 64% and increases to 89% with daily once-daily administration.

For a dose of 20 mg esomeprazole, these figures are 50% and 68%, respectively. Plasma protein binding is 97%.

Esomeprazole is metabolized by the cytochrome P450 system. The main part is metabolized with the participation of the specific polymorphic isoenzyme CYP2C19, resulting in the formation of hydroxylated and demethylated metabolites of esomeprazole.

The metabolism of the remaining part is carried out by the isoenzyme CYP3A4; this produces the sulfo derivative of esomeprazole, which is the main metabolite determined in plasma.

The total clearance is approximately 17 L/h after a single dose of esomeprazole and 9 L/h after multiple doses. T_1/2 is 1.3 hours with systematic administration in a once-daily dosing regimen.

AUC increases with multiple doses (non-linear dose and AUC relationship with systematic administration, which is a consequence of reduced first-pass metabolism through the liver, as well as a decrease in systemic clearance caused by inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfur-containing metabolite).

It does not accumulate. Up to 80% of the dose is excreted by the kidneys as metabolites (less than 1% unchanged), the rest is excreted in the bile.

With daily IV administration once a day, Esomeprazole is completely eliminated from the blood plasma during the interval between administrations; no tendency for esomeprazole accumulation is noted.

With repeated IV administration of esomeprazole at a dose of 40 mg, the average C_max in blood plasma is approximately 13.6 µmol/L. The overall exposure increases slightly less (by approximately 30%) with IV administration of esomeprazole compared to oral administration.

When esomeprazole was administered IV at doses of 40 mg, 80 mg, and 120 mg over 30 minutes followed by IV administration at a dose of 4 mg/h or 8 mg/h for 23.5 hours, a linear dependence of AUC on the administered dose was demonstrated.

Indications

Gastroesophageal reflux disease: erosive reflux esophagitis (treatment), prevention of relapses in patients with healed esophagitis, symptomatic treatment of GERD.

As part of combination therapy: eradication of Helicobacter pylori, duodenal ulcer associated with Helicobacter pylori, prevention of recurrence of peptic ulcers in patients with peptic ulcer disease associated with Helicobacter pylori.

Long-term acid-suppressive therapy in patients who have suffered from peptic ulcer bleeding (after IV use of drugs that reduce gastric gland secretion, to prevent recurrence).

For healing of gastric ulcer associated with NSAID use.

Prevention of gastric and duodenal ulcers associated with NSAID use in patients at risk.

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

For the prevention of recurrent bleeding from a peptic ulcer after endoscopic hemostasis (for IV administration).

In children (aged 1 year to 18 years) as an alternative to oral therapy when it is not possible – for gastroesophageal reflux disease in patients with erosive reflux esophagitis and/or severe symptoms of reflux disease (for IV administration).

ICD codes

Dosage Regimen

Administer orally or intravenously. Set the dosage regimen individually based on indication, clinical condition, and patient age.

For Gastroesophageal Reflux Disease (GERD): administer 20 mg or 40 mg orally once daily for 4-8 weeks. For long-term management of healed esophagitis, use 20 mg once daily.

For Helicobacter pylori eradication: use as part of a combination therapy regimen. Administer 20 mg esomeprazole twice daily with amoxicillin 1000 mg and clarithromycin 500 mg, both twice daily, for 7-14 days.

For healing of gastric ulcers associated with NSAIDs: administer 20 mg or 40 mg orally once daily for 4-8 weeks.

For prevention of gastric and duodenal ulcers associated with NSAIDs in at-risk patients: administer 20 mg or 40 mg orally once daily.

For Zollinger-Ellison syndrome: initiate therapy at 40 mg orally twice daily. Adjust the dose individually; most patients are managed on 80-160 mg daily. For doses exceeding 80 mg daily, divide into two administrations.

For intravenous administration when oral therapy is not possible: administer a injection or infusion of 20 mg or 40 mg once daily. Do not exceed the recommended dose and duration.

For pediatric patients aged 1-11 years with GERD (IV only, when oral therapy not possible): use a dose of 10 mg for body weight less than 55 kg or 20 mg for body weight 55 kg or more, once daily.

For adolescents aged 12-18 years: use the adult oral dose for GERD.

Swallow tablets whole with water. Do not crush or chew. Take at least one hour before food, typically before breakfast.

For patients with severe hepatic impairment, a maximum daily dose of 20 mg is recommended. No dose adjustment is required for renal impairment or for elderly patients.

The duration of treatment depends on the indication. Do not use for longer than recommended. For long-term therapy, regularly monitor the patient’s clinical status.

Adverse Reactions

Skin and subcutaneous tissue disorders: uncommon – dermatitis, pruritus, rash, urticaria; rare – alopecia, photosensitivity; very rare – erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: rare – arthralgia, myalgia; very rare – muscle weakness.

Nervous system disorders: common – headache; uncommon – dizziness, paresthesia, somnolence, disorientation; rare – taste disturbance.

Psychiatric disorders: uncommon – insomnia; rare – depression, agitation, confusion; very rare – hallucinations, aggressive behavior.

Gastrointestinal disorders: common – abdominal pain, constipation, diarrhea, flatulence, nausea, vomiting; uncommon – dry mouth; rare – stomatitis, gastrointestinal candidiasis; very rare – microscopic colitis (histologically confirmed).

Hepatobiliary disorders: uncommon – increased liver enzyme activity; rare – hepatitis; very rare – hepatic failure, encephalopathy in patients with liver disease.

Reproductive system and breast disorders: very rare – gynecomastia.

Blood and lymphatic system disorders: rare – leukopenia, thrombocytopenia; very rare – agranulocytosis, pancytopenia.

Immune system disorders: rare – hypersensitivity reactions (including fever, angioedema, anaphylactic reactions/anaphylactic shock).

Respiratory, thoracic and mediastinal disorders: rare – bronchospasm.

Renal and urinary disorders: very rare – interstitial nephritis.

Eye disorders: rare – blurred vision.

Metabolism and nutrition disorders: uncommon – peripheral edema; rare – hyponatremia; very rare – hypomagnesemia; hypocalcemia due to severe hypomagnesemia, hypokalemia due to hypomagnesemia.

General disorders and administration site conditions: rare – malaise, hyperhidrosis.

Contraindications

Hypersensitivity to esomeprazole; children under 12 years of age and children over 12 years of age for indications other than gastroesophageal reflux disease (for oral administration); children under 1 year of age and children under 18 years of age for indications other than gastroesophageal reflux disease (for IV administration); breastfeeding period.

Concomitant use of esomeprazole with atazanavir and nelfinavir is contraindicated.

With caution

Severe renal impairment.

Use in Pregnancy and Lactation

Use during pregnancy is possible only if the expected benefit of therapy for the mother outweighs the potential risk to the fetus. Contraindicated for use during breastfeeding.

Use in Hepatic Impairment

Should be used with caution in severe hepatic impairment. Dose adjustment may be required.

Use in Renal Impairment

Should be used with caution in severe renal impairment. Dose adjustment may be required.

Pediatric Use

Contraindicated in children under 12 years of age and children over 12 years of age for indications other than gastroesophageal reflux disease (for oral administration); in children under 1 year of age and children under 18 years of age for indications other than gastroesophageal reflux disease (for IV administration).

Geriatric Use

When using proton pump inhibitors, especially at high doses and for prolonged periods (>1 year), the risk of fractures of the hip, wrist, and vertebrae increases, especially in elderly patients.

Special Precautions

In the presence of symptoms such as significant spontaneous weight loss, frequent vomiting, dysphagia, vomiting blood or melena, as well as in the presence (or suspicion) of a gastric ulcer, the possibility of a malignant neoplasm should be excluded, since treatment with esomeprazole may alleviate symptoms and thus delay the correct diagnosis.

During long-term therapy, the patient’s condition should be regularly monitored.

During treatment with proton pump inhibitors, plasma gastrin levels increase as a result of reduced intragastric hydrochloric acid secretion. In patients taking proton pump inhibitors for a long time, the formation of glandular cysts in the stomach is more often observed. These phenomena are due to physiological changes resulting from the inhibition of hydrochloric acid secretion.

Esomeprazole, like all acid-reducing drugs, can lead to reduced absorption of vitamin B₁₂ due to hypo- or achlorhydria. This should be considered in patients with risk factors for reduced vitamin B₁₂ absorption during long-term therapy.

When using proton pump inhibitors, especially at high doses and for prolonged periods (>1 year), the risk of fractures of the hip, wrist, and vertebrae increases (especially in elderly patients).

Esomeprazole can cause an increase in chromogranin A levels, which may distort the results of examinations for neuroendocrine tumors. Treatment with esomeprazole should be temporarily discontinued at least 5 days before determining chromogranin A.

Effect on ability to drive vehicles and operate machinery

During the use of esomeprazole, patients should exercise caution when driving vehicles and operating machinery, as well as when engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Drug Interactions

It is believed that concomitant use may increase plasma concentrations and enhance the effects of imipramine, clomipramine, citalopram.

It is believed that concomitant use may decrease plasma concentrations and clinical efficacy of itraconazole and ketoconazole.

With concomitant use with clarithromycin, a case of significant increase in the AUC of esomeprazole due to inhibition of its metabolism under the influence of clarithromycin has been described.

With concomitant use, an increase in plasma concentrations of diazepam and phenytoin is possible, which apparently has no clinical significance.

Reduced secretion of hydrochloric acid in the stomach during treatment with esomeprazole and other proton pump inhibitors may lead to decreased or increased absorption of drugs whose absorption depends on environmental acidity.

With concomitant use of omeprazole and saquinavir, an increase in the plasma concentration of saquinavir was noted.

With concomitant use of esomeprazole and tacrolimus, an increase in the plasma concentration of tacrolimus was noted.

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

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

There is evidence that concomitant use of esomeprazole with clarithromycin, which inhibits the CYP3A4 isoenzyme, leads to a 2-fold increase in the AUC value of esomeprazole. Concomitant use of esomeprazole and a combined inhibitor of CYP3A4 and CYP2C19 isoenzymes, for example, voriconazole, may lead to a more than 2-fold increase in the AUC value for esomeprazole.

Drugs that induce CYP2C19 and CYP3A4 isoenzymes, such as rifampicin and St. John’s wort preparations, when used concomitantly with esomeprazole, may lead to a decrease in the plasma concentration of esomeprazole due to accelerated metabolism.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.