Diaprazol 40

Pharmaceutical form.

Lyophilized powder for solution for injection.

Main physicochemical properties: white or almost white free-flowing mass and/or granular powder.

Pharmacotherapeutic group.

Drugs for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors.

ATC Code A02B C01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Omeprazole, a racemic mixture of two enantiomers, reduces gastric acid secretion through a mechanism of highly targeted action. Omeprazole inhibits gastric acid secretion by specifically affecting the proton pump in parietal cells. The drug acts rapidly when administered once daily and provides control through reversible inhibition of gastric acid secretion.

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

Pharmacodynamic effects

All pharmacodynamic effects can be explained by the effect of omeprazole on gastric acid secretion.

Effect on gastric acid secretion

Intravenous administration of omeprazole causes dose-dependent inhibition of gastric acid secretion in humans. To immediately reduce intragastric acidity to a level comparable to that achieved with repeated 20 mg oral doses, the recommended initial intravenous dose is 40 mg. This leads to immediate reduction of intragastric acidity and sustained suppression of this parameter by an average of 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 time.

No signs of tachyphylaxis have been observed during omeprazole therapy.

Effect on H. pylori

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

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

Other effects related to inhibition of gastric acid secretion

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

Increased number of ECL cells, possibly related to increased serum gastrin levels, has been observed in both children and adults during long-term omeprazole therapy. These data are considered to be of no clinical significance.

During long-term treatment, slightly increased frequency of gastric polyps has been reported. These changes are a physiological consequence of pronounced inhibition of gastric acid secretion; this process is benign and likely reversible.

Reducing gastric acidity by any means, including proton pump inhibitors, increases the number of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing agents may lead to a slightly increased risk of gastrointestinal infections caused by Salmonella and Campylobacter.

Pharmacokinetics.

Distribution

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

Metabolism and elimination

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 depends on 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 low affinity for CYP3A4, omeprazole does not have the ability to inhibit the metabolism of other CYP3A4 substrates. Additionally, omeprazole does not inhibit major CYP enzymes.

Approximately 3% of Caucasian and 15–20% of Mongoloid individuals lack functional CYP2C19 enzyme; they are referred to as "poor metabolizers." In these individuals, omeprazole metabolism may be primarily catalyzed by the CYP3A4 enzyme. After repeated administration of omeprazole at a dose of 20 mg once daily, the mean AUC value in "poor metabolizers" is 5–10 times higher than in individuals with functional CYP2C19 enzyme ("extensive metabolizers"). The mean maximum plasma concentration was also 3–5 times higher. However, these results do not affect omeprazole dosing.

Elimination

Total plasma clearance is approximately 30–40 L/h after a single dose. The plasma half-life of omeprazole is usually less than one hour after both single and repeated once-daily administration. Omeprazole is completely cleared from plasma between doses without tendency to accumulate when administered once daily. Almost 80% of the omeprazole dose is excreted in urine as metabolites, and the remainder in feces, primarily via biliary secretion.

The AUC of omeprazole increases with repeated administration. This increase is dose-dependent and results in non-linear AUC-dose relationship 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). No metabolite has been shown to affect gastric acid secretion.

Special patient groups

Patients with hepatic impairment

Metabolism of omeprazole is slowed in patients with hepatic impairment, leading to increased AUC. No tendency toward accumulation was observed with once-daily omeprazole administration.

Patients with renal impairment

Pharmacokinetics of omeprazole, including systemic bioavailability and elimination rate, are not altered in patients with impaired renal function.

Elderly patients

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

Clinical characteristics.

Indications.

DIAZOL 40 for intravenous use is indicated as an alternative to oral therapy for the following indications.

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.

DIAZOL 40, like other proton pump inhibitors (PPIs), should not be used concomitantly with nelfinavir and atazanavir (see section "Interaction with other medicinal products and other types of interactions ").

Interaction with other medicinal products and other types of interactions.

Effect of omeprazole on pharmacokinetics of other medicinal products

Medicinal products whose absorption depends on gastric pH

Inhibition of gastric secretion during omeprazole and other PPI therapy may reduce or increase absorption of medicinal products whose absorption depends on gastric pH. As with other agents that reduce intragastric acidity, absorption of drugs such as ketoconazole, itraconazole, and erlotinib may be reduced, while absorption of drugs such as digoxin may be increased during omeprazole therapy. It has been reported that concomitant administration of omeprazole (20 mg daily) and digoxin increases digoxin bioavailability by 10%.

Nelfinavir, atazanavir

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

Concomitant use of omeprazole and nelfinavir is contraindicated.

Concomitant administration of omeprazole (40 mg once daily) reduces the average exposure to nelfinavir by approximately 40%, and the average exposure to its pharmacologically active metabolite M8 is reduced by approximately 75–90%. The interaction may also be due to inhibition of CYP2C19 activity.

Concomitant use of omeprazole with atazanavir is not recommended.

Concomitant administration of omeprazole (40 mg once daily) with atazanavir 300 mg or ritonavir 100 mg results in a 75% reduction in atazanavir exposure. Increasing the atazanavir dose to 400 mg does not compensate for the effect of omeprazole on atazanavir exposure. Concomitant administration of omeprazole (20 mg once daily) with atazanavir 400 mg or ritonavir 100 mg results in approximately 30% reduction in atazanavir exposure compared to atazanavir 300 mg or ritonavir 100 mg once daily.

Digoxin

Concomitant treatment with omeprazole (20 mg daily) and digoxin increases digoxin bioavailability by 10%. Rare cases of digoxin toxicity have been reported. However, caution should be exercised when prescribing high doses of omeprazole to elderly patients. Therapeutic drug monitoring of digoxin should be intensified.

Clopidogrel

When clopidogrel and omeprazole are used together, exposure to the active metabolite of clopidogrel decreases from day 1 to day 5 from 46% to 42%. Mean inhibition of platelet aggregation decreases from 47% to 30% from day 1 to day 5 when clopidogrel and omeprazole are used together. Administration of clopidogrel and omeprazole at different times does not prevent their interaction, likely due to omeprazole's inhibitory effect on CYP2C19. Conflicting data have been reported regarding the clinical implications of this PK/PD interaction in terms of major cardiovascular events.

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

DIAZOL 40 is a moderate inhibitor of CYP2C19, the main enzyme metabolizing omeprazole. Thus, metabolism of concomitant medicinal products metabolized by CYP2C19 may be reduced, and systemic exposure to these agents may increase. Examples include R-warfarin and other vitamin K antagonists, cilostazol, diazepam, and phenytoin.

Studies in healthy volunteers demonstrated a pharmacokinetic/pharmacodynamic interaction between clopidogrel (loading dose – 300 mg/maintenance dose – 75 mg daily) and omeprazole (80 mg daily orally, i.e., a dose four times higher than the standard daily dose), resulting in a mean 46% reduction in exposure to the active metabolite of clopidogrel and a mean 16% reduction in maximum inhibitory effect (ADP-induced) of platelet aggregation. As a precaution, concomitant use of omeprazole and clopidogrel should be avoided.

However, it remains unclear to what extent this interaction may have clinical significance. There is no evidence of increased risk of cardiovascular thromboembolic events with concomitant use of clopidogrel and PPIs, including esomeprazole.

A number of observational studies have shown conflicting results regarding whether the risk of cardiovascular thromboembolic events increases when a patient receives clopidogrel together with a PPI.

It has been reported that administration of clopidogrel in combination with acetylsalicylic acid and esomeprazole compared to clopidogrel monotherapy resulted in nearly a 40% reduction in exposure to the active metabolite of clopidogrel. However, maximum inhibitory activity against (ATP-induced) platelet aggregation in these individuals was similar in groups receiving clopidogrel alone and in combination with acetylsalicylic acid and esomeprazole, likely due to concomitant administration of low-dose acetylsalicylic acid.

Cilostazol

Administration of omeprazole at a dose of 40 mg increases Cmax and AUC of cilostazol by 18% and 26%, respectively, and one of its active metabolites by 29% and 69%, respectively.

Phenytoin

Monitoring of phenytoin plasma concentration is recommended during the first two weeks after initiation of omeprazole therapy; and if the phenytoin dose is adjusted, monitoring and further dose adjustment should be performed after discontinuation of omeprazole therapy.

Unknown mechanism

Saquinavir

Concomitant use 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

Increased serum levels of tacrolimus have been reported with concomitant use of omeprazole. Intensified monitoring of tacrolimus concentration and renal function (creatinine clearance) is required, and dose adjustment of tacrolimus may be necessary.

Methotrexate

Increased methotrexate levels have been reported in some patients when used concomitantly with proton pump inhibitors. When high-dose methotrexate is required, temporary discontinuation of omeprazole should be considered.

Effect of other medicinal products on omeprazole pharmacokinetics

Inhibitors of CYP2C19 and/or CYP3A4

Since omeprazole is metabolized by CYP2C19 and CYP3A4 enzymes, drugs known to inhibit the activity of CYP2C19 or CYP3A4, or both enzymes (such as clarithromycin and voriconazole), may lead to increased omeprazole serum levels due to slowed metabolism rate. Concomitant use of voriconazole resulted in more than twofold increase in omeprazole exposure. Since high omeprazole doses were well tolerated, dose adjustment of omeprazole is usually not required. However, dose adjustment should be considered for patients with severe hepatic impairment and during long-term therapy.

DIAZOL 40 is also partially metabolized by CYP3A4 but does not inhibit this enzyme. Thus, omeprazole does not affect the metabolism of drugs metabolized by CYP3A4, such as cyclosporine, lidocaine, quinidine, estradiol, erythromycin, and budesonide.

Inducers of CYP2C19 and/or CYP3A4

Drugs known to 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 rate.

Special precautions.

In the presence of any alarming symptom (e.g., significant unintentional weight loss, recurrent vomiting, dysphagia, hematemesis, or melena) and in suspicion or presence of gastric ulcer, malignancy must be ruled out, as treatment may reduce symptom severity and delay diagnosis.

A pharmacokinetic/pharmacodynamic interaction between clopidogrel (loading dose – 300 mg/maintenance dose – 75 mg daily) and omeprazole (80 mg daily orally, i.e., a dose four times higher than the standard daily dose) has been reported, resulting in a mean 46% reduction in exposure to the active metabolite of clopidogrel and a mean 16% reduction in maximum inhibitory effect (ADP-induced) of platelet aggregation.

Concomitant use of atazanavir with proton pump inhibitors is not recommended. If a combination of atazanavir with a proton pump inhibitor cannot be avoided, careful clinical monitoring (e.g., viral load) is recommended in combination with increasing the atazanavir dose to 400 mg with 100 mg ritonavir; the omeprazole dose should not exceed 20 mg.

DIAZOL 40, like all medicinal products that inhibit gastric acid secretion, may reduce absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered for patients with cachexia or risk factors for reduced vitamin B12 absorption during long-term therapy.

DIAZOL 40 is an inhibitor of CYP2C19. At the start or upon discontinuation of omeprazole therapy, potential interactions with medicinal products metabolized by CYP2C19 should be considered. An interaction occurs between clopidogrel and omeprazole. The clinical significance of this interaction remains unclear. As a precaution, concomitant use of omeprazole and clopidogrel should be avoided.

Treatment with proton pump inhibitors may lead to a slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter.

As with any long-term treatment, especially when the treatment period with DIAZOL 40 exceeds 1 year, patients should be under regular monitoring.

Some published studies suggest that proton pump inhibitor (PPI) therapy may be associated with a small increased risk of osteoporosis-related fractures.

However, other similar observational studies have not found an increased risk.

In randomized, double-blind, controlled studies using omeprazole and esomeprazole (including two open long-term studies involving individuals aged 12 years and older), no association between PPI use and osteoporosis-related fractures was found.

Despite the lack of proven causal relationship between omeprazole/esomeprazole and osteoporotic fractures, patients at risk of progressive osteoporosis or osteoporotic fractures should be advised appropriate clinical monitoring according to current clinical guidelines for this condition.

Use during pregnancy or breastfeeding.

Studies have been reported indicating no adverse effect of DIAZOL 40 on pregnancy or fetal/neonatal health. DIAZOL 40 can be used during pregnancy.

DIAZOL 40 is excreted in breast milk but is unlikely to affect the infant when used at therapeutic doses.

Ability to affect reaction rate when driving or operating machinery.

It is unlikely that DIAZOL 40 affects the ability to drive or operate machinery. Adverse reactions such as dizziness and visual disturbances may occur. If such disorders occur, patients should not drive or operate machinery.

Method and dosage.

Dosage

Alternative to oral therapy

For patients for whom oral formulation is unsuitable, DIAZOL 40 40 mg once daily intravenously is recommended. For patients with Zollinger-Ellison syndrome, the recommended initial intravenous dose is 60 mg daily. Higher daily doses may be required, so the dose should be individually adjusted. If the dose exceeds 60 mg daily, it should be divided equally into two parts and administered twice daily.

The drug should be administered intravenously only and must not be given by any other route.

The solution should be used immediately after preparation, but no later than 4 hours. The diluted solution of DIAZOL 40 must not be stored in the refrigerator. Unused solution should be discarded.

Instructions for reconstitution prior to administration

For intravenous injections: the contents of each vial of DIAZOL 40 containing 40 mg omeprazole should be dissolved in 10 mL of sterile water for injection. The solution for intravenous injection should be administered slowly (over 5 minutes).

For intravenous infusions: the contents of each vial of DIAZOL 40 containing 40 mg omeprazole should be reconstituted in 10 mL and then diluted to 100 mL with 0.9% sodium chloride solution or 5% glucose solution. Omeprazole stability depends on the pH of the infusion solution; therefore, other solvents or volumes should not be used for dilution.

The solution for intravenous infusion should be administered over 20–30 minutes.

The solution should be used immediately after preparation, but no later than 4 hours. The diluted omeprazole solution must not be stored in the refrigerator.

Any unused product or waste should be disposed of according to local requirements.

Special patient categories

Renal impairment

Dose adjustment is not required for patients with renal impairment.

Hepatic impairment

Patients with hepatic impairment may require a daily dose of 10–20 mg.

Elderly patients (>65 years)

Dose adjustment is not required for elderly patients.

Children.

Experience with intravenous administration of the drug in pediatric practice is limited; therefore, the drug should not be prescribed to this patient group.

Overdose.

Information on the consequences of omeprazole overdose in humans is limited. Cases of administration up to 560 mg have been described; isolated reports of single oral doses of omeprazole up to 2400 mg (120 times higher than the usual recommended clinical dose) have also been received. Reported cases include nausea, vomiting, dizziness, abdominal pain, diarrhea, and headache. Isolated cases have also reported lethargy, depression, and confusion.

The described symptoms were temporary, and no reports of serious consequences have been received. Drug elimination rate did not change (first-order kinetics) with increasing doses.

If necessary, symptomatic treatment should be administered.

In clinical trials, intravenous administration of the drug up to 270 mg in one day and up to 650 mg over three days did not result in any dose-dependent adverse reactions.

Adverse reactions.

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

During clinical trials of omeprazole and in the post-marketing period, the following adverse drug reactions were identified. None of these events were considered dose-dependent. The adverse reactions listed below are classified by frequency and by system organ classes (SOC). Frequency is defined as follows: 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), frequency not known (cannot be estimated from available data).

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

Shelf life. 2 years.

The prepared solution should be stored at a temperature not exceeding 25°C and used within 4 hours.

From a microbiological standpoint, the product should be used immediately, except when reconstitution is carried out under controlled and aseptic conditions validated by appropriate methods.

Storage conditions.

Store at a temperature not exceeding 25°C in the original packaging, protected from light. Keep out of reach of children.

Incompatibilities. This medicinal product must not be mixed with other medicinal products except those mentioned in the section “Administration and dosage”.

Packaging. Powder for solution for injection in a vial. One vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Reyoung Pharmaceutical Co., Ltd.

Reyoung Pharmaceutical Co., Ltd.

Marketing Authorization Holder. GRIN BUSINESS SOLUTIONS SA / GREEN BUSINESS SOLUTIONS SA

Address of the manufacturer. No.1, Ruiyang Road, Yiyuan County, Shandong Province, People's Republic of China

No.1 Ruiyang Road, Yiyuan County, Shandong Province, P.R.China

Address of the marketing authorization holder:

Rue Mercerie 12, c/o Drys Fiduciaire SA, 1003 Lausanne, Switzerland

Rue Mercerie 12, c/o Drys Fiduciaire SA, 1003 Lausanne, Switzerland