Esom^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Hetero Labs, Limited (India)

Manufactured By

Aspiro Pharma, Limited (India)

Packaging and Quality Control Release

ASPIRO PHARMA, Limited (India)

Or

MAKIZ-PHARMA, LLC (Russia)

ATC Code

A02BC05 (Esomeprazole)

Active Substance

Esomeprazole (Rec.INN WHO registered)

Dosage Form

Esom®

Lyophilizate for preparation of solution for intravenous administration 40 mg: fl. 10 pcs.

Dosage Form, Packaging, and Composition

Lyophilizate for preparation of solution for intravenous administration in the form of a lyophilized mass from white to almost white.

Excipients: disodium edetate dihydrate – 1.5 mg, sodium hydroxide solution 1 M – to pH 11.40-11.8.

40 mg – colorless glass vials (type I) with a volume of 5 ml (10) – cardboard boxes.

Clinical-Pharmacological Group

H⁺-K⁺-ATPase inhibitor

Pharmacotherapeutic Group

Gastric secretion reducing agent – proton pump inhibitor

Pharmacological Action

H⁺-K⁺-ATPase inhibitor, the dextrorotatory isomer of omeprazole. 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 parietal cells of the gastric mucosa, 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/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 administration once/day. For a dose of 20 mg 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 dosing regimen of once/day. 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). 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 intravenous administration once/day, Esomeprazole is completely eliminated from the blood plasma in the interval between administrations, and no tendency for esomeprazole accumulation is noted. With repeated intravenous 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 somewhat less (by approximately 30%) with intravenous administration of esomeprazole compared with oral administration.

With intravenous administration of esomeprazole in doses of 40 mg, 80 mg and 120 mg over 30 minutes followed by intravenous 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 cured 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 intravenous use of drugs that reduce gastric secretion, to prevent recurrence).

For healing of gastric ulcers 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 intravenous administration).

In children (aged 1 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 intravenous administration).

ICD codes

Dosage Regimen

Administer intravenously as a slow injection or infusion. Use only when oral therapy is not appropriate. Transition to oral formulation at the earliest opportunity.

Reconstitute the 40 mg vial with 5 mL of 0.9% Sodium Chloride Injection. Do not use other solvents. Gently shake the vial until the lyophilisate is completely dissolved. Inspect the solution visually for particulate matter and discoloration before administration. The reconstituted solution is stable for 12 hours at room temperature (up to 30°C).

For intravenous injection: Administer the prepared solution slowly over a period of at least 3 minutes.

For intravenous infusion: Further dilute the reconstituted solution in 100 mL of 0.9% Sodium Chloride Injection. Administer the infusion over a period of 10 to 30 minutes. Flush the intravenous line with 0.9% Sodium Chloride Injection before and after administration to ensure complete delivery.

For Gastroesophageal Reflux Disease in patients without esophagitis: The recommended dose is 20 mg or 40 mg intravenously once daily.

For erosive reflux esophagitis: The recommended dose is 40 mg intravenously once daily.

For Helicobacter pylori eradication: Use as part of a combination regimen. The recommended dose is 40 mg intravenously once daily with amoxicillin and clarithromycin for 10 days.

For prevention of recurrent peptic ulcer bleeding after endoscopic hemostasis: Administer an 80 mg intravenous bolus over 30 minutes, followed by a continuous intravenous infusion of 8 mg per hour for 72 hours.

For Zollinger-Ellison syndrome and other hypersecretory conditions: The recommended initial dose is 40 mg intravenously twice daily. Adjust the dosage regimen individually based on acid output measurements. Doses up to 240 mg daily have been used.

For pediatric patients aged 1 to 18 years with GERD when oral therapy is not possible: The recommended dose is 10 mg for patients weighing less than 20 kg; 20 mg for patients weighing 20 kg or more. Administer intravenously once daily.

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

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 system disorders rare – arthralgia, myalgia; very rare – muscle weakness.

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

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

Digestive system 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 activity of liver enzymes; rare – hepatitis; very rare – liver failure, encephalopathy in patients with liver disease.

Reproductive system disorders very rare – gynecomastia.

Hematopoietic system disorders: rare – leukopenia, thrombocytopenia; very rare – agranulocytosis, pancytopenia.

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

Respiratory system disorders rare – bronchospasm.

Urinary system 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 rare – malaise, sweating.

Contraindications

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

Concomitant use of esomeprazole with atazanavir and nelfinavir is contraindicated.

With caution

Severe renal failure.

Use in Pregnancy and Lactation

Use during pregnancy is possible in cases where the expected benefit of therapy for the mother outweighs the possible 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 other indications except gastroesophageal reflux disease (for oral administration); in children under 1 year of age and children under 18 years of age for other indications except gastroesophageal reflux disease (for intravenous administration).

Geriatric Use

When using proton pump inhibitors, especially when used in high doses and for a long 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 smooth out the 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, the level of gastrin in the plasma increases 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 drugs that reduce acidity, can lead to a decrease in the absorption of vitamin B₁₂ due to hypo- or achlorhydria. This should be taken into account in patients with risk factors for reduced absorption of vitamin B₁₂ during long-term therapy.

When using proton pump inhibitors, especially when used in high doses and for a long period (>1 year), the risk of fractures of the hip, wrist and vertebrae increases (especially in elderly patients).

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

Effect on ability to drive vehicles and machinery

During the use of esomeprazole, patients should be careful when driving vehicles and 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 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 the 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 the concentration of methotrexate was noted when used concomitantly with proton pump inhibitors. When using high doses of methotrexate, the possibility of temporary withdrawal 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 the 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, can 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, can lead to a decrease in the plasma concentration of esomeprazole due to accelerated metabolism.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°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.