Omeprazole-abryl

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Omeprazole-Abryl (Omeprazole-Abryl)

Composition:

Active substance: omeprazole;

1 vial contains sodium omeprazole equivalent to omeprazole 40 mg;

Excipients: edetate disodium, sodium hydroxide.

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical properties: lyophilized powder or cake ranging from white to almost white.

Pharmacotherapeutic group.
Agents for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. Omeprazole. ATC code A02BC01.

Pharmacological properties.

Pharmacodynamics.

Omeprazole, a racemic mixture of two enantiomers, reduces gastric hydrochloric acid secretion through an extremely targeted mechanism of action. Omeprazole inhibits gastric acid secretion by specifically acting on the proton pump in parietal cells. When administered once daily, the drug acts rapidly and provides control through reversible suppression of gastric juice hydrochloric acid secretion.

Omeprazole is a weak base that accumulates and is converted into its active form in the highly acidic environment of intracellular canaliculi of parietal cells, where it inhibits the H+, K+-ATPase enzyme (proton pump). This effect on the final step of gastric juice hydrochloric acid formation is dose-dependent and provides highly effective inhibition of both basal and stimulated acid secretion, regardless of the type of stimulation.

All pharmacodynamic effects can be explained by the influence of omeprazole on hydrochloric acid secretion.

Effect on gastric acid secretion

Intravenous administration of omeprazole causes dose-dependent inhibition of gastric acid secretion in humans. To achieve an immediate reduction in intragastric acidity equivalent to that obtained with repeated oral doses of 20 mg omeprazole, an initial intravenous dose of 40 mg omeprazole is recommended. This results in an immediate reduction of intragastric acidity and sustained maintenance of this reduction, averaging 90% over 24 hours, both after intravenous injection and intravenous infusion.

Inhibition of acid secretion correlates with the area under the plasma concentration-time curve (AUC) of omeprazole and does not depend on the actual plasma concentration of omeprazole at any given moment.

No signs of tachyphylaxis have been observed during omeprazole treatment.

Effect on Helicobacter pylori (H. pylori)

H. pylori is associated with the development of peptic ulcer disease, including duodenal and gastric ulcers. H. pylori is the primary factor in the development of gastritis. H. pylori, together with gastric hydrochloric acid, is a major factor in the development of peptic ulcer disease. H. pylori is also the main factor in the development of atrophic gastritis, which is associated with an increased risk of gastric cancer.

Eradication of H. pylori using omeprazole in combination with antimicrobial agents is associated with high rates of ulcer healing and prolonged remission.

Other effects related to inhibition of gastric acid secretion

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Additionally, chromogranin A (CgA) levels increase due to reduced gastric acidity. Elevated CgA levels may interfere with diagnostic testing for neuroendocrine tumors. It has been reported that treatment with proton pump inhibitors (PPIs) should be discontinued 5–14 days before CgA measurement. Testing should be repeated if levels have not normalized by that time.

An increase in ECL cells, possibly related to elevated serum gastrin levels, has been observed in both children and adults during long-term omeprazole treatment. These findings are considered to have no clinical significance.

During prolonged treatment courses, a slightly increased frequency of gastric fundic gland polyps has been reported. These changes are a physiological consequence of pronounced inhibition of gastric acid secretion; the process is benign and likely reversible. Reduction of gastric acidity by any means, including PPIs, increases the number of bacteria normally present in the gastrointestinal tract. The use of acid-reducing agents may lead to a slightly increased risk of gastrointestinal infections caused by Salmonella and Campylobacter.

Pharmacokinetics.

The apparent volume of distribution in healthy volunteers is approximately 0.3 L/kg body weight. Omeprazole is approximately 97% bound to plasma proteins.

Omeprazole is completely metabolized by the cytochrome P450 (CYP) system. The majority of its metabolism depends on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the main metabolite in plasma. The remainder is metabolized by another specific isoenzyme (CYP3A4), responsible for the formation of omeprazole sulfone. Due to omeprazole's high affinity for CYP2C19, there is potential for competitive inhibition and metabolic drug-drug interactions with other CYP2C19 substrates. However, due to its low affinity for CYP3A4, omeprazole does not inhibit the metabolism of other CYP3A4 substrates. Furthermore, omeprazole does not inhibit major CYP enzymes.

Approximately 3% of individuals of Caucasian ethnicity and 15–20% of individuals of Mongoloid ethnicity lack functional CYP2C19 enzyme and are classified as poor metabolizers. In these individuals, omeprazole metabolism may be primarily catalyzed by CYP3A4. After repeated administration of omeprazole 20 mg once daily, the mean AUC in poor metabolizers is 5–10 times higher than in individuals with functional CYP2C19 (extensive metabolizers). The average maximum plasma concentration is also higher—by 3–5 times. However, these findings do not affect omeprazole dosing.

Total plasma clearance is approximately 30–40 L/h after a single dose. The elimination half-life of omeprazole in plasma is generally less than 1 hour, both after single and repeated once-daily administration. Omeprazole is completely eliminated from plasma between doses, with no tendency for accumulation when administered once daily. Nearly 80% of an omeprazole dose is excreted in urine as metabolites, and the remainder is excreted in feces, primarily via biliary secretion.

The AUC of omeprazole increases with repeated administration. This increase is dose-dependent and results in a nonlinear relationship between AUC and dose after repeated dosing. This time- and dose-dependent relationship is due to reduced presystemic metabolism and systemic clearance, possibly caused by inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (e.g., sulfone). None of the metabolites have been shown to affect gastric juice hydrochloric acid secretion.

Patients with hepatic impairment

Omeprazole metabolism is slowed in patients with impaired liver function, leading to increased AUC. However, with omeprazole administered once daily, no tendency toward drug accumulation has been observed.

Patients with renal impairment

The pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are not altered in patients with reduced renal function.

Elderly patients

The rate of omeprazole metabolism is slightly reduced in elderly patients (75–79 years of age).

Clinical characteristics.

Indications.

Intravenous omeprazole is indicated as an alternative to oral therapy for the following conditions.

Adults

• Treatment of duodenal ulcer.
• Prevention of recurrence of duodenal ulcer.
• Treatment of gastric ulcer.
• Prevention of recurrence of gastric ulcer.
• In combination with appropriate antibiotics for eradication of Helicobacter pylori (H. pylori) in peptic ulcer disease.
• Treatment of gastric and duodenal ulcers associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs).
• Prevention of gastric and duodenal ulcers associated with NSAID use in high-risk patients.
• Treatment of reflux esophagitis.
• Long-term treatment of patients with inactive reflux esophagitis.
• Treatment of symptomatic gastroesophageal reflux disease.
• Treatment of Zollinger-Ellison syndrome.

Contraindications.

Hypersensitivity to omeprazole, substituted benzimidazoles, or to any of the excipients of the medicinal product.

Concomitant use of omeprazole, as with other proton pump inhibitors (PPIs), with nelfinavir and atazanavir is contraindicated.

Interaction with other medicinal products and other forms of interaction.

Effect of omeprazole on the pharmacokinetics of other medicinal products

Medicinal products whose absorption is pH-dependent

Reduced gastric acidity during omeprazole treatment may increase or decrease the absorption of active substances whose bioavailability is pH-dependent.

Nelfinavir, atazanavir

Plasma levels of nelfinavir and atazanavir are reduced when administered concomitantly with omeprazole.

Concomitant use of omeprazole with nelfinavir is contraindicated (see section "Special precautions for use"). Concomitant administration of omeprazole (40 mg once daily) reduced the average exposure to nelfinavir by approximately 40%, and the exposure to its pharmacologically active metabolite M8 decreased by approximately 75–90%. The interaction may also involve inhibition of CYP2C19.

Concomitant use of omeprazole with atazanavir is not recommended (see section "Special precautions for use"). Concomitant administration of omeprazole (40 mg once daily) with atazanavir 300 mg/ritonavir 100 mg in healthy volunteers resulted in a 75% reduction in atazanavir exposure. Increasing the atazanavir dose to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Concomitant administration of omeprazole (20 mg once daily) with atazanavir 400 mg/ritonavir 100 mg in healthy volunteers resulted in approximately 30% reduction in atazanavir exposure compared to atazanavir 300 mg/ritonavir 100 mg once daily.

Digoxin

Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy volunteers increased digoxin bioavailability by 10%. Digoxin toxicity has been rarely reported. However, omeprazole should be used with caution at high doses in elderly patients. Therapeutic monitoring of digoxin should be intensified thereafter.

Clopidogrel

In a crossover clinical study, clopidogrel (300 mg loading dose followed by 75 mg daily) was administered alone and with omeprazole (80 mg given simultaneously with clopidogrel) for 5 days. Exposure to the active metabolite of clopidogrel was reduced by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were co-administered. Mean inhibition of platelet aggregation was reduced by 47% (24 hours) and 30% (Day 5) with concomitant use of clopidogrel and omeprazole. In another study, administration of clopidogrel and omeprazole at different times did not prevent their interaction, which is likely due to omeprazole's inhibitory effect on CYP2C19. Observational and clinical studies have reported conflicting data regarding the clinical consequences of this pharmacokinetic/pharmacodynamic interaction in terms of serious cardiovascular events. As a precautionary measure, concomitant use of omeprazole and clopidogrel should be avoided (see section "Special precautions for use").

Other medicinal products

Absorption of posaconazole, erlotinib, ketoconazole, and itraconazole is significantly reduced; therefore, clinical efficacy may be diminished. Concomitant use with posaconazole and erlotinib should be avoided.

Medicinal products metabolized by CYP2C19

Omeprazole is a moderate inhibitor of CYP2C19, the main enzyme responsible for omeprazole metabolism. Thus, metabolism of concomitantly administered active substances that are also metabolized by CYP2C19 may be reduced, and systemic exposure to these substances may be increased. Examples include R-warfarin and other vitamin K antagonists, cilostazol, diazepam, and phenytoin.

Cilostazol

In a crossover study, administration of omeprazole 40 mg to healthy volunteers increased the maximum concentration (Cmax) and AUC of cilostazol by 18% and 26%, respectively, and of one of its active metabolites by 29% and 69%, respectively.

Phenytoin

Plasma phenytoin concentration monitoring is recommended during the first 2 weeks after initiation of omeprazole treatment. If phenytoin dose adjustment is required, monitoring and further dose adjustments should continue after discontinuation of omeprazole.

Unknown mechanism

Saquinavir

Concomitant administration of omeprazole with saquinavir/ritonavir resulted in an increase in saquinavir plasma levels by approximately 70%, which was associated with acceptable tolerability in HIV-infected patients.

Tacrolimus

Elevated serum tacrolimus levels have been reported with concomitant use of omeprazole. Intensified monitoring of tacrolimus concentrations, as well as renal function (creatinine clearance), is required, and dose adjustment of tacrolimus should be considered if necessary.

Methotrexate

Elevated methotrexate levels have been reported in some patients when co-administered with PPIs. In cases where high-dose methotrexate is required, temporary discontinuation of omeprazole should be considered.

Effect of other medicinal products on the pharmacokinetics of omeprazole

Inhibitors of CYP2C19 and/or CYP3A4

Since omeprazole is metabolized by CYP2C19 and CYP3A4, active substances known to inhibit CYP2C19 or CYP3A4 (such as clarithromycin and voriconazole) may lead to increased omeprazole serum levels by reducing its metabolic rate. Concomitant treatment with voriconazole resulted in more than a twofold increase in omeprazole exposure. Since high doses of omeprazole are generally well tolerated, dose adjustment of omeprazole is usually not required. However, dose adjustment should be considered in patients with severe hepatic impairment and in cases where long-term treatment is indicated.

Inducers of CYP2C19 and/or CYP3A4

Medicinal products that induce the activity of CYP2C19 or CYP3A4, or both enzymes (such as rifampicin and St. John's wort), may lead to decreased omeprazole serum levels due to accelerated metabolism.

Special precautions for use.

In the presence of any alarming symptom (e.g., significant unintentional weight loss, recurrent vomiting, dysphagia, hematemesis, or melena) and in suspected or confirmed gastric ulcer, malignancy must be ruled out, as treatment may mask symptoms and delay diagnosis. Concomitant use of atazanavir with PPIs is contraindicated. If a combination of atazanavir with a PPI cannot be avoided, careful clinical monitoring (e.g., viral load) is recommended, along with increasing the atazanavir dose to 400 mg with 100 mg ritonavir; the omeprazole dose should not exceed 20 mg.

Omeprazole, like all medicinal products that suppress gastric acid secretion, may reduce absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with cachexia or risk factors for reduced vitamin B12 absorption during long-term therapy.

Omeprazole is an inhibitor of CYP2C19. At the initiation or discontinuation of omeprazole treatment, potential interactions with medicinal products metabolized via CYP2C19 should be considered. An interaction has been observed between clopidogrel and omeprazole. The clinical significance of this interaction remains unclear. As a precautionary measure, concomitant use of omeprazole and clopidogrel should be avoided.

PPI treatment may lead to a slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter, and possibly also Clostridium difficile in hospitalized patients (see section "Pharmacodynamics"). Severe hypomagnesemia has been reported in patients receiving PPIs, such as omeprazole, for at least three months, and in most cases, for over a year. Serious manifestations of hypomagnesemia, such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia, may occur and may present insidiously. In most patients, hypomagnesemia resolves upon magnesium supplementation and discontinuation of PPI therapy.

For patients expected to undergo long-term PPI therapy or those taking PPIs with digoxin or other medicinal products that may cause hypomagnesemia (e.g., diuretics), magnesium levels should be measured before starting PPI therapy and periodically during treatment.

The use of PPIs, particularly at high doses and over prolonged periods (>1 year), is associated with a slightly increased risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other risk factors. Study data indicate that PPIs increase the overall fracture risk by 10–40%. In some cases, this is associated with the presence of other risk factors in the patient. Patients at risk of osteoporosis should receive appropriate treatment and adequate supplementation with vitamin D and calcium.

Subacute cutaneous lupus erythematosus (SCLE)

PPI use has occasionally been associated with the development of SCLE. If skin manifestations appear, particularly in sun-exposed areas and accompanied by arthralgia, patients should seek immediate medical advice and discontinuation of omeprazole should be considered. A history of SCLE following omeprazole use increases the risk of SCLE with other PPIs.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels may interfere with diagnostic tests for neuroendocrine tumors. To avoid this interference, omeprazole should be temporarily discontinued at least 5 days before CgA measurement (see section "Pharmacodynamics"). If CgA and gastrin levels have not returned to reference ranges after initial measurements, these parameters should be re-measured 14 days after discontinuation of the medicinal product.

Patients receiving long-term omeprazole therapy (particularly if treatment exceeds 1 year) should be under regular medical supervision. Renal function impairment

Acute tubulointerstitial nephritis (ATIN) has been observed in patients taking omeprazole and may occur at any time during omeprazole therapy (see section "Adverse reactions"). Acute tubulointerstitial nephritis may progress to renal failure.

If ATIN is suspected, omeprazole should be discontinued and appropriate treatment initiated immediately.

Important information about excipients

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy

Results from three prospective epidemiological studies (over 1000 pregnancy outcomes) indicate no adverse effects of omeprazole on pregnancy or fetal/newborn health. Omeprazole may be used during pregnancy.

Breastfeeding

Omeprazole is excreted in breast milk, but the risk to the infant is unlikely if the mother is taking the medicinal product at therapeutic doses.

Fertility

Animal studies with the racemic mixture of omeprazole did not indicate effects on fertility.

Ability to influence reaction speed when driving or operating machinery.

Omeprazole is unlikely to affect the ability to drive or operate machinery. However, adverse reactions such as dizziness and visual disturbances may occur. If such symptoms occur, patients should not drive or operate machinery.

Method of Administration and Dosage

Dosage

Alternative to Oral Therapy

For patients for whom oral omeprazole is not suitable, Omeprazole-Abril 40 mg is recommended to be administered intravenously once daily. For patients with Zollinger-Ellison syndrome, the recommended initial intravenous dose of omeprazole is 60 mg per day. Higher daily doses may be required; therefore, the dose should be individually adjusted. If the daily dose exceeds 60 mg, it should be divided equally into two doses and administered twice daily. The medicinal product should be given as a 20–30 minute intravenous infusion.

Instructions for Reconstitution Prior to Administration

The entire contents of each vial should be dissolved in approximately 5 mL of solvent and then immediately diluted to a final volume of 100 mL. Use either 0.9% sodium chloride solution or 5% glucose solution. The stability of omeprazole depends on the pH of the infusion solution; therefore, no other solvent or volume should be used for reconstitution.

Preparation

1. Using a syringe, withdraw 5 mL of infusion solution from a 100 mL infusion bag or bottle.
2. Add this volume to the vial containing lyophilized omeprazole and mix thoroughly to ensure complete dissolution of the drug.
3. Withdraw the omeprazole solution back into the syringe.
4. Transfer the solution into the infusion bag or bottle.
5. Repeat steps 1–4 to ensure that the entire omeprazole content has been transferred from the vial into the infusion bag or bottle.

Alternative Method for Preparing Infusion Solution in a Flexible Container

1. Attach a double-ended transfer needle to the injection site of the infusion bag. Connect the other end of the needle to the vial containing lyophilized omeprazole.
2. Dissolve the omeprazole by passing the infusion solution back and forth between the infusion bag and the vial.
3. Ensure complete dissolution of the drug.

The resulting solution should be used for intravenous infusion within 20–30 minutes.

Any unused medicinal product or waste material must be disposed of in accordance with local requirements.

Renal Impairment

Dose adjustment is not required in patients with renal impairment.

Hepatic Impairment

In patients with hepatic impairment, a daily dose of omeprazole of 10–20 mg may be sufficient.

Elderly Patients (> 65 years)

Dose adjustment is not required in elderly patients.

Children

Experience with intravenous omeprazole in pediatric practice is limited; therefore, the medicinal product should not be administered to this age group.

Overdose

Symptoms. Information on omeprazole overdose in humans is limited. Cases of omeprazole administration at doses up to 560 mg have been reported. There have also been isolated reports of single oral doses of omeprazole reaching 2400 mg (120 times higher than the usual recommended dose). Symptoms observed included nausea, vomiting, dizziness, abdominal pain, diarrhea, and headache. In isolated cases, apathy, depression, and confusion have also been reported. The described symptoms were transient, and no serious outcomes have been reported.

Treatment. The elimination rate of omeprazole does not change (first-order kinetics) with increasing doses. If necessary, symptomatic treatment should be administered.

In clinical trials, omeprazole was administered intravenously at doses up to 270 mg in a single day and up to 650 mg over 3 days, without resulting in any dose-dependent adverse reactions.

Adverse reactions.

The most common adverse reactions (in 1–10 % of patients) are headache, abdominal pain, constipation, diarrhea, flatulence, and nausea/vomiting.

During clinical studies with omeprazole and in the post-marketing period, the adverse drug reactions listed below have been identified. None of the adverse reactions were considered dose-dependent. The adverse reactions listed below are classified by frequency and by organ systems. Frequencies are defined according to the following categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and not known (cannot be estimated from the available data).

In isolated cases, irreversible vision impairment has been reported in critically ill patients receiving omeprazole as intravenous injection, particularly at high doses; however, a causal relationship has not been established.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Shelf life of the reconstituted solution: up to 6 hours at a temperature not exceeding 25 ºC.

Incompatibilities.

The medicinal product must not be mixed with other medicinal products except those mentioned in the section "Instructions for use and dosage".

Packaging.

1 or 10 vials with powder in a cardboard package.

Prescription status. Prescription only.

Manufacturer.

Abhil Laboratories Private Limited.

Manufacturer's address and site of operation.

Village Bhagwanpur, Tehsil Dera Bassi, District Sahibzada Ajit Singh Nagar, Punjab – 140507, India.