Emanera^® (Capsules) Instructions for Use

ATC Code

A02BC05 (Esomeprazole)

Active Substance

Esomeprazole (Rec.INN WHO registered)

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 the 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 activates 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 daily, 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 plasma is reached in 1-2 hours. The absolute bioavailability of esomeprazole after a single 40 mg dose is 64% and increases to 89% with daily once-daily administration.

For the 20 mg dose of 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, forming 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 and reduced systemic clearance caused by inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfonated 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 daily, Esomeprazole is completely eliminated from the plasma in the interval between administrations, and no tendency for accumulation of esomeprazole is noted.

With repeated IV administration of esomeprazole at a dose of 40 mg, the average C_max in plasma is approximately 13.6 µmol/L. The overall exposure increases somewhat 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 shown.

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 had bleeding from a peptic ulcer (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 the 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. Swallow capsules whole with water; do not chew or crush.

Take at least one hour before meals.

For erosive reflux esophagitis: 40 mg once daily for 4 weeks. For unhealed esophagitis, continue for an additional 4 weeks.

For long-term prevention of relapse in patients with healed esophagitis: 20 mg once daily.

For symptomatic GERD without esophagitis: 20 mg once daily for 4 weeks. If symptoms persist after 4 weeks, investigate further.

For H. pylori eradication: Use as part of a combination regimen. One example is esomeprazole 20 mg, amoxicillin 1 g, and clarithromycin 500 mg, all taken twice daily for 7 days.

For healing of NSAID-associated gastric ulcer: 20 mg to 40 mg once daily for 4 to 8 weeks.

For prevention of NSAID-associated gastric and duodenal ulcers in patients at risk: 20 mg once daily.

For Zollinger-Ellison syndrome: The recommended initial dose is 40 mg twice daily. Adjust dose individually; most patients are controlled with 80 mg to 160 mg daily. Doses exceeding 80 mg should be divided.

For patients with severe liver impairment, a maximum daily dose of 20 mg is recommended.

Do not use in children under 12 years of age, except for GERD in adolescents aged 12-17 years, for which the dose is 20 mg or 40 mg once daily for up to 8 weeks.

Adverse Reactions

From the skin and subcutaneous tissues uncommon – dermatitis, pruritus, rash, urticaria; rare – alopecia, photosensitivity; very rare – erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

From the musculoskeletal system rare – arthralgia, myalgia; very rare – muscle weakness.

From the nervous system common – headache; uncommon – dizziness, paresthesia, somnolence, disorientation; rare – taste disturbance.

From the psyche uncommon – insomnia; rare – depression, agitation, confusion; very rare – hallucinations, aggressive behavior.

From the digestive system common – abdominal pain, constipation, diarrhea, flatulence, nausea, vomiting; uncommon – dry mouth; rare – stomatitis, gastrointestinal candidiasis; very rare – microscopic colitis (histologically confirmed).

From the liver and biliary tract uncommon – increased activity of liver enzymes; rare – hepatitis; very rare – liver failure, encephalopathy in patients with liver disease.

From the reproductive system very rare – gynecomastia.

From the hematopoietic system: rare – leukopenia, thrombocytopenia; very rare – agranulocytosis, pancytopenia.

From the immune system rare – hypersensitivity reactions (including fever, angioedema, anaphylactic reactions/anaphylactic shock).

From the respiratory system rare – bronchospasm.

From the urinary system very rare – interstitial nephritis.

From the organ of vision rare – blurred vision.

From metabolism uncommon – peripheral edema; rare – hyponatremia; very rare – hypomagnesemia; hypocalcemia due to severe hypomagnesemia, hypokalemia due to hypomagnesemia.

General reactions rare – malaise, sweating.

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 a prolonged period (>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 secretion of hydrochloric acid. In patients taking proton pump inhibitors for a long time, the formation of glandular cysts in the stomach is more often noted. These phenomena are due to physiological changes as a result of inhibition of hydrochloric acid secretion.

Esomeprazole, like all acid-reducing drugs, may 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 a prolonged period (>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 the determination of chromogranin A.

Effect on ability to drive vehicles and mechanisms

During the use of esomeprazole, patients should exercise caution when driving vehicles and mechanisms, 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 with simultaneous use, an increase in plasma concentrations and enhancement of the effects of imipramine, clomipramine, and citalopram is possible.

It is believed that with simultaneous use, a decrease in plasma concentrations and clinical effectiveness of itraconazole and ketoconazole is possible.

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

With simultaneous 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 a decrease or increase in the absorption of drugs whose absorption depends on environmental acidity.

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

With simultaneous 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 with 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.