Rediomez^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Dr. Reddy’s Laboratories Ltd. (India)

Manufactured By

Gland Pharma, Limited (India)

ATC Code

A02BC05 (Esomeprazole)

Active Substance

Esomeprazole (Rec.INN WHO registered)

Dosage Form

Rediomez®

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 porous mass or powder from white to almost white.

Excipients: disodium edetate – 1.5 mg, sodium hydroxide – 0.2-1 mg.

Colorless glass vials with a capacity of 5 ml – (1) – cardboard packs.

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 specific inhibition of 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 dependence of dose and AUC 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 sulfa-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.

When esomeprazole was administered intravenously at 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 demonstrated.

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 peptic ulcer bleeding (after intravenous use of drugs that reduce gastric secretion, to prevent relapse).

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 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 intravenous administration).

ICD codes

Dosage Regimen

Administer intravenously. Reconstitute the 40 mg lyophilisate only with 0.9% Sodium Chloride Injection. Do not use other solvents. Inject 5 ml of diluent into the vial. Gently swirl until the powder is completely dissolved. Do not shake. Inspect the resulting solution for particulate matter and discoloration before administration. Discard if not clear and colorless.

For intravenous infusion, further dilute the reconstituted solution in 100 ml of 0.9% Sodium Chloride Injection. Administer as an intravenous infusion over 10 to 30 minutes. Do not administer as an intravenous bolus.

For Gastroesophageal Reflux Disease with erosive esophagitis, administer 40 mg once daily. For symptomatic GERD without esophagitis, administer 20 mg once daily. The recommended treatment duration is 4 to 8 weeks.

For the prevention of rebleeding of peptic ulcers following endoscopic hemostasis, administer an 80 mg intravenous bolus infusion over 30 minutes, followed by a continuous intravenous infusion at a rate of 8 mg per hour for 72 hours.

For Helicobacter pylori eradication, use as part of a combination regimen. Administer 40 mg once daily with amoxicillin 1000 mg and clarithromycin 500 mg, all given twice daily for 10 to 14 days.

For Zollinger-Ellison syndrome and other hypersecretory conditions, the initial dose is 40 mg twice daily. Adjust the dosage individually; doses up to 240 mg daily have been used.

For pediatric patients aged 1 to 18 years with GERD, the recommended dose is 10 mg for weight less than 55 kg and 20 mg for weight 55 kg or greater, administered once daily. Use only when oral therapy is not possible or appropriate.

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

Switch to oral therapy with a proton pump inhibitor as soon as clinically appropriate. The total duration of intravenous therapy should be as short as possible and not exceed 10 days.

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, somnolence, 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 (confirmed histologically).

Hepatobiliary disorders uncommon – increased activity of liver enzymes; rare – hepatitis; very rare – hepatic 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 only if 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 failure. Dose adjustment may be required.

Pediatric Use

Contraindicated for use 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 lead to smoothing of 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 drugs that reduce acidity, can lead to reduced 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 may distort the results of examinations for neuroendocrine tumors. Treatment with esomeprazole should be temporarily suspended at least 5 days before the determination of 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 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 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 when used concomitantly 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.