Prazol

CHARACTERISTICS OF THE MEDICINAL PRODUCT

1. NAME OF THE MEDICINAL PRODUCT

PRAZOL, 40 mg, gastro-resistant hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 40 mg of omeprazole (Omeprazolum).
Excipients with known effect: each capsule contains 160.05 mg of sucrose.
For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Gastro-resistant hard capsule
The gastro-resistant hard capsule of Prazol consists of an orange body with the imprint "40" and a blue cap with the imprint "O".

4. CLINICAL PARTICULARS

4.1 Therapeutic Indications

Prazol is indicated for the following uses:
Adults:

• Treatment of duodenal ulcer disease.
• Prevention of duodenal ulcer recurrence.
• Treatment of gastric ulcer disease.
• Prevention of gastric ulcer recurrence.
• Eradication of Helicobacter pylori infection in patients with gastric and duodenal ulcer disease, in combination with appropriate antibiotics.
• Treatment of gastric and duodenal ulcer disease caused by non-steroidal anti-inflammatory drugs (NSAIDs).
• Prevention of gastric and duodenal ulcer disease caused by non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk.
• Treatment of reflux esophagitis.
• Long-term treatment of patients with healed reflux esophagitis.
• Symptomatic treatment of gastroesophageal reflux disease.
• Treatment of Zollinger-Ellison syndrome.

Children and adolescents:
Children over 1 year of age and with a body weight of ≥ 10 kg:

• Treatment of reflux esophagitis.
• Symptomatic treatment of heartburn and acid regurgitation in gastroesophageal reflux disease. Children and adolescents over 4 years of age:
• Treatment of duodenal ulcer disease caused by Helicobacter pylori, in combination with antibiotics.

4.2 Posology and Method of Administration

Dosage
Adults
Treatment of duodenal ulcer disease
The recommended dose for patients with active duodenal ulcer is 20 mg once daily. Most patients heal within 2 weeks of starting treatment. For patients who are not fully healed after the initial treatment period, healing usually occurs within 2 additional weeks of therapy. For patients with duodenal ulcer disease that is resistant to treatment, a dose of 40 mg once daily is recommended; for these patients, healing usually occurs within 4 weeks.
Prevention of duodenal ulcer recurrence
In preventing duodenal ulcer recurrence in patients with a negative test result for Helicobacter pylori or when eradication of Helicobacter pylori is not possible, the recommended dose is 20 mg once daily. For some patients, a dose of 10 mg once daily may be sufficient. If therapy fails, the dose may be increased to 40 mg.
Treatment of gastric ulcer disease
The recommended dose is 20 mg once daily. Most patients heal within 4 weeks of starting treatment. For patients who are not fully healed after the initial treatment period, healing usually occurs within 4 additional weeks of therapy. For patients with gastric ulcer disease that is resistant to treatment, a dose of 40 mg once daily is recommended; for these patients, healing usually occurs within 8 weeks.
Prevention of gastric ulcer recurrence
In preventing recurrence in patients with gastric ulcer disease that is resistant to treatment, the recommended dose is 20 mg once daily. If necessary, the dose may be increased to 40 mg once daily.
Eradication of Helicobacter pylori infection in patients with gastric and duodenal ulcer disease
The choice of antibiotic for Helicobacter pylori eradication should be made on an individual basis, taking into account the patient's tolerance and local, regional, and national guidelines for antibiotic resistance.

• 20 mg omeprazole + 500 mg clarithromycin + 1000 mg amoxicillin, each given twice daily for 1 week or
• 20 mg omeprazole + 250 mg clarithromycin (alternatively 500 mg) + 400 mg metronidazole (or 500 mg or 500 mg tinidazole), each given twice daily for 1 week or
• 40 mg omeprazole once daily, 500 mg amoxicillin, and 400 mg metronidazole (or 500 mg or 500 mg tinidazole), each given three times daily for 1 week. If, after completion of therapy according to any of the above regimens, the infection with Helicobacter pylori persists, treatment can be repeated.

Treatment of gastric and duodenal ulcer disease caused by non-steroidal anti-inflammatory drugs (NSAIDs)
Prevention of gastric and duodenal ulcer disease caused by non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk
The recommended dose for the treatment of gastric and duodenal ulcer disease caused by NSAIDs is 20 mg once daily. Most patients heal within 4 weeks of starting treatment. For patients who are not fully healed after the initial treatment period, healing usually occurs within 4 additional weeks of therapy.
Treatment of reflux esophagitis
The recommended dose is 20 mg once daily. Most patients heal within 4 weeks of starting treatment. For patients who are not fully healed after the initial treatment period, healing usually occurs within 4 additional weeks of therapy. For patients with severe esophagitis, a dose of 40 mg once daily is recommended; for these patients, healing usually occurs within 8 weeks.
Long-term treatment of patients with healed reflux esophagitis
The recommended dose for long-term treatment of patients with healed reflux esophagitis is 10 mg once daily. If necessary, the dose may be increased to 20-40 mg once daily.
Symptomatic treatment of gastroesophageal reflux disease
The recommended dose is 20 mg once daily. For some patients, a dose of 10 mg may be sufficient; therefore, individual dose adjustment should be considered for each patient. If symptoms do not resolve after 4 weeks of treatment with a dose of 20 mg once daily, further investigations should be performed.
Treatment of Zollinger-Ellison syndrome
For patients with Zollinger-Ellison syndrome, the dose should be individualized, and treatment should be continued as long as clinically indicated. The recommended initial dose is 60 mg once daily. For more than 90% of patients with severe symptoms who are poorly responsive to other treatments, maintenance therapy with a dose of 20-120 mg once daily is usually effective. Omeprazole doses greater than 80 mg once daily should be given in two divided doses.
Children and adolescents
Children over 1 year of age and with a body weight of ≥ 10 kg
Treatment of reflux esophagitis.
Symptomatic treatment of heartburn and acid regurgitation in gastroesophageal reflux disease.
The recommended dosages are as follows:
Reflux esophagitis:treatment duration is 4-8 weeks.
Symptomatic treatment of heartburn and acid regurgitation in gastroesophageal reflux disease:treatment duration is 2-4 weeks. If symptoms do not resolve after 2-4 weeks, further investigations should be performed.

Children and adolescents over 4 years of age
Treatment of duodenal ulcer disease caused by Helicobacter pylori
When selecting an appropriate combination therapy, national, regional, and local guidelines for resistance, treatment duration (usually 7 days, but sometimes up to 14 days), and the appropriate use of antibacterial agents should be considered. Treatment should be carried out under the supervision of a specialist.
The recommended dosages are as follows:
Special populations
Dosage in renal impairment
No dose adjustment is necessary for patients with renal impairment (see section 5.2). Dosage in hepatic impairmentFor patients with hepatic impairment, a dose of 10-20 mg once daily may be sufficient (see section 5.2). Dosage in elderly patients (> 65 years)No dose adjustment is necessary for elderly patients (see section 5.2).

• 5.2). Dosage in hepatic impairmentFor patients with hepatic impairment, a dose of 10-20 mg once daily may be sufficient (see section 5.2). Dosage in elderly patients (> 65 years)No dose adjustment is necessary for elderly patients (see section 5.2).

Method of administration
Prazol should be taken in the morning, preferably on an empty stomach. The capsules should be swallowed whole with half a glass of water. The capsules should not be chewed or crushed.
Patients with difficulty swallowing and children who can drink or swallow semi-solid food
The capsule can be opened and the contents taken with half a glass of water or mixed with a slightly acidic liquid, such as fruit juice or apple sauce, or non-carbonated water.
The patient should be informed that the resulting mixture should be taken immediately (or within 30 minutes of preparation). The mixture should always be stirred before taking and followed by half a glass of water.
The capsule can also be sucked, and then the pellets swallowed with half a glass of water.
The enteric-coated pellets should not be chewed.

4.3 Contraindications

Hypersensitivity to the active substance, substituted benzimidazoles, or any of the excipients listed in section 6.1.
Omeprazole, like other proton pump inhibitors, should not be used concomitantly with nelfinavir.

4.4 Special Warnings and Precautions for Use

In the event of any alarming symptoms (e.g., significant, unexpected weight loss, recurrent vomiting, difficulty swallowing, bloody vomiting, or black stools) and in cases of gastric ulcer disease or suspected gastric ulcer disease, the presence of a malignant disease should be excluded before starting treatment, as omeprazole may mask symptoms and delay a proper diagnosis.
Concomitant use of atazanavir with proton pump inhibitors is not recommended (see section 4.5). If combination therapy of atazanavir and a proton pump inhibitor is necessary, close clinical monitoring is recommended, with an increased dose of atazanavir to 400 mg with ritonavir 100 mg; a dose of more than 20 mg omeprazole should not be used.
Omeprazole, like all medications that reduce gastric acid secretion, may reduce the absorption of vitamin B12 (cyanocobalamin) due to the lack of acid or achlorhydria. This should be considered in patients with vitamin B12 deficiency and in the presence of risk factors for reduced vitamin B12 absorption during long-term treatment.
Omeprazole is a CYP2C19 inhibitor. When starting and stopping omeprazole therapy, the possibility of interactions with medications metabolized by CYP2C19 should be considered. Interactions have been observed between clopidogrel and omeprazole (see section 4.5). The clinical significance of this interaction is uncertain. As a precaution, the concomitant use of omeprazole and clopidogrel should be avoided.
Proton pump inhibitors, especially when used in high doses and over long periods (more than 1 year), may slightly increase the risk of hip, wrist, and spine fractures, particularly in older people or patients with other risk factors for osteoporosis. The results of studies suggest that proton pump inhibitors may increase the overall risk of fractures by 10-40%. This may also be due to other risk factors. Patients with a risk of osteoporosis should receive care according to current clinical guidelines and should take an appropriate dose of vitamin D and calcium.

Hypomagnesemia

In patients treated with proton pump inhibitors (PPIs), such as omeprazole, for at least three months, and in most patients taking PPIs for one year, cases of severe hypomagnesemia have been reported. Severe hypomagnesemia may cause symptoms such as fatigue, tetany, delirium, dizziness, and cardiac arrhythmias, but these may start insidiously and remain unnoticed. In severely affected patients, hypomagnesemia improved after magnesium replacement and discontinuation of the proton pump inhibitor.
For patients in whom long-term therapy is anticipated or who are taking a proton pump inhibitor concomitantly with digoxin or other medications that may cause hypomagnesemia (e.g., diuretics), consideration should be given to monitoring magnesium levels before starting proton pump inhibitor therapy and periodically during treatment.

Subacute Cutaneous Lupus Erythematosus (SCLE)

The use of proton pump inhibitors has been associated with the rare occurrence of SCLE. If skin lesions occur, especially in sun-exposed areas, with arthralgia, the patient should seek medical help immediately, and the doctor should consider discontinuing Prazol.
The occurrence of SCLE with a previous proton pump inhibitor may increase the risk of SCLE with other proton pump inhibitors.
Treatment with proton pump inhibitors may slightly increase the risk of gastrointestinal infections with bacteria, such as Salmonella and Campylobacter (see section 5.1).
As with all long-term therapies, especially those lasting more than 1 year, patients should be kept under regular medical supervision.
Effect on laboratory tests
An increase in chromogranin A (CgA) levels may interfere with investigations for neuroendocrine tumors. To avoid this, Prazol treatment should be stopped for at least 5 days before measuring CgA levels (see section 5.1). If, after initial measurement, CgA and gastrin levels are still above the reference range, measurements should be repeated 14 days after discontinuation of proton pump inhibitor therapy.
The product contains sucrose.
Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption syndrome, or sucrase-isomaltase insufficiency should not take this medicinal product.
Children and adolescents
Some children with chronic diseases may require long-term therapy, although such therapy is not recommended.
The product contains less than 1 mmol of sodium (23 mg) per tablet, which is considered to be essentially sodium-free.

4.5 Interaction with Other Medicinal Products and Other Forms of Interaction

Effect of omeprazole on the pharmacokinetics of other active substances
Active substances with pH-dependent absorption
The reduced acidity of the gastric juice during omeprazole treatment may increase or decrease the absorption of active substances whose absorption is pH-dependent.
Nelfinavir, atazanavir
Concomitant use of nelfinavir and atazanavir with omeprazole reduces the plasma concentrations of these medications.
Concomitant use of omeprazole with nelfinavir is contraindicated (see section 4.3).
Administration of omeprazole (in a single daily dose of 40 mg) results in a decrease in the mean exposure to nelfinavir by about 40% and to its pharmacologically active metabolite M8 by about 75-90%. This interaction may also involve inhibition of CYP2C19.
Concomitant use of omeprazole with atazanavir is not recommended (see section 4.4). Concomitant administration of omeprazole (in a single daily dose of 40 mg) and atazanavir (in a dose of 300 mg) or ritonavir (in a dose of 100 mg) resulted in a 75% reduction in the exposure to atazanavir in healthy volunteers. Increasing the dose of atazanavir to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Concomitant administration of omeprazole (in a single daily dose of 20 mg) and atazanavir (in a dose of 400 mg) or ritonavir (in a dose of 100 mg) in healthy volunteers resulted in a decrease in atazanavir exposure by about 30%, compared to the effect of atazanavir (in a dose of 300 mg) or ritonavir (in a dose of 100 mg) given once daily.
Digoxin
Concomitant administration of omeprazole (in a dose of 20 mg once daily) and digoxin in healthy volunteers showed a 10% increase in digoxin bioavailability. Rarely, toxic effects of digoxin have been observed. However, caution should be exercised when using omeprazole in high doses in elderly patients. In this case, monitoring of digoxin effects should be considered.
Clopidogrel
In a crossover clinical study, clopidogrel (loading dose 300 mg, then 75 mg once daily) was given alone or with omeprazole (80 mg, given with clopidogrel) for 5 days. When clopidogrel and omeprazole were given concomitantly, the mean exposure to the active metabolite of clopidogrel was reduced by 46% (Day 1) and 42% (Day 5). Concomitant administration of clopidogrel and omeprazole resulted in a 47% reduction in the mean inhibition of platelet aggregation (IPA) (after 24 hours) and 30% (Day 5). The results of another study showed that the administration of clopidogrel and omeprazole at different times of the day did not prevent the interaction between these medications, which is likely due to the inhibition of CYP2C19 by omeprazole. In observational studies and clinical trials, inconsistent data have been reported regarding the clinical significance of this PK/PD interaction, regarding the occurrence of serious cardiovascular events.
Other active substances
The absorption of posaconazole, erlotinib, ketoconazole, and itraconazole is significantly reduced, which may impair their clinical effectiveness. Concomitant use of posaconazole and erlotinib should be avoided.
Active substances metabolized by CYP2C19
Omeprazole is a moderate inhibitor of CYP2C19, the main enzyme responsible for the metabolism of this medication. Therefore, the metabolic processes of concomitantly administered active substances that are also metabolized by CYP2C19 may be slowed, resulting in increased exposure to these active substances. Examples of such medications include R-warfarin and other vitamin K antagonists, cilostazol, diazepam, and phenytoin.
Cilostazol
In a crossover study, administration of omeprazole (in a dose of 40 mg) to healthy volunteers resulted in an increase in the Cmax and AUC of cilostazol by 18% and 26%, respectively, as well as an increase in the Cmax and AUC of one of the active metabolites of cilostazol by 29% and 69%, respectively.
Phenytoin
It is recommended to monitor phenytoin plasma levels during the first 2 weeks of omeprazole treatment and when the dose of phenytoin is changed, and to adjust the dose as necessary during and after omeprazole treatment.
Unknown mechanism of action
Saquinavir
Concomitant administration of omeprazole and saquinavir/ritonavir resulted in increased saquinavir plasma concentrations to about 70%, with good tolerance in HIV patients.
Tacrolimus
Concomitant administration of tacrolimus and omeprazole resulted in increased tacrolimus plasma concentrations. Close monitoring of tacrolimus plasma levels and renal function (creatinine clearance) is recommended, with appropriate dose adjustment of tacrolimus.
Effect of other active substances on the pharmacokinetics of omeprazole
Inhibitors of CYP2C19 and/or CYP3A4
Since omeprazole is metabolized by CYP2C19 and CYP3A4, the use of active substances with known ability to inhibit CYP2C19 or CYP3A4 (such as clarithromycin and voriconazole) may lead to increased omeprazole plasma concentrations through reduced metabolism of this medication. Concomitant administration of voriconazole resulted in more than a twofold increase in omeprazole exposure. Due to the good tolerance of omeprazole in such high doses, dose adjustment is not required. However, dose adjustment should be considered in patients with severe hepatic impairment and in cases where long-term therapy is necessary.
Inducers of CYP2C19 and/or CYP3A4
The use of active substances that induce CYP2C19, CYP3A4, or both (such as rifampicin and St. John's Wort) may lead to decreased omeprazole plasma concentrations through increased metabolism of this medication.

4.6 Fertility, Pregnancy, and Lactation

Pregnancy
The results of three prospective epidemiological studies (over 1000 outcomes) have shown that omeprazole does not have a detrimental effect on pregnancy, the fetus, or the newborn. Omeprazole may be used during pregnancy.
Breast-feeding
Omeprazole is excreted in breast milk, but at therapeutic doses, its effect on the child is unlikely.

4.7 Effects on Ability to Drive and Use Machines

Prazol is unlikely to affect the ability to drive or operate machinery. However, side effects such as dizziness and visual disturbances (see section 4.8) may occur. If a patient experiences these side effects, they should not drive or operate machinery.

4.8 Undesirable Effects

The most common undesirable effects (1-10% of patients) are headache, abdominal pain, constipation, diarrhea, bloating, and nausea/vomiting.
The following undesirable effects have been reported or are suspected to have occurred during clinical trials and after the marketing of omeprazole:
No undesirable effect has been found to be related to the dose.
Undesirable effects are presented by frequency and system organ class. The frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 to <1>

Children and adolescents
The safety of omeprazole has been evaluated in 310 children aged 0-16 years with acid-related diseases. Limited long-term safety data are available for 46 children who received maintenance therapy with omeprazole for up to 749 days. The profile of undesirable effects was generally similar to that in adult patients treated with short-term and long-term therapy. Long-term data on the effects of omeprazole on growth and puberty are not available.
Reporting of suspected undesirable effects
After the marketing of the medicinal product, it is important to report any suspected undesirable effects. Healthcare professionals are asked to report any suspected undesirable effects via the national reporting system:
Department for the Surveillance of Adverse Reactions to Medicinal Products, Urząd Rejestracji Produktów Leczniczych, Wyrobów Medycznych i Produktów Biobójczych, Al. Jerozolimskie 181C, 02-222 Warszawa, tel.: +48 22 49-21-301, fax: +48 22 49-21-309, website: https://smz.ezdrowie.gov.pl .
Undesirable effects can also be reported to the marketing authorization holder.

4.9 Overdose

Data on omeprazole overdose in humans are limited. In the literature, cases of omeprazole overdose have been reported, with doses up to 560 mg and single reports of a single dose of up to 2,400 mg omeprazole (120 times the recommended clinical dose). The symptoms observed after omeprazole overdose are: nausea, vomiting, dizziness of central origin, abdominal pain, diarrhea, and headache. In individual cases, apathy, depression, and confusion have also been reported.
All symptoms reported after omeprazole overdose were transient and did not result in serious clinical consequences after they resolved. Increased doses of omeprazole did not change the rate of elimination of the medicinal product (first-order kinetics). Symptomatic treatment should be applied if necessary.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Proton pump inhibitors, ATC code: A02BC01
Mechanism of action
Omeprazole is a racemic mixture of two active enantiomers. It causes a reduction in gastric acid secretion by a highly selective mechanism of action. It is a specific inhibitor of the proton pump in gastric parietal cells. The action of omeprazole is rapid and provides control through reversible inhibition of gastric acid secretion when administered once daily.
Omeprazole is a weak base that achieves high concentrations in the acidic environment of the parietal cell canaliculi. It is converted to its active form and inhibits the activity of one of the proton pump enzymes - H+,K+-ATPase.
The effect on the final stage of gastric acid production is dose-dependent and provides effective inhibition of gastric acid secretion, both basal and stimulated, regardless of the stimulating factor.
Pharmacodynamic effects
The observed pharmacodynamic effect of omeprazole can be explained by its effect on gastric acid secretion.
Effect on gastric acid secretion
Oral administration of omeprazole once daily provides rapid and effective inhibition of gastric acid secretion throughout the day, with maximum effect occurring after 4 days of omeprazole administration. After this period of omeprazole administration at a dose of 20 mg per day in patients with duodenal ulcers, there is a reduction in mean daily gastric acidity of about 80%. The mean reduction in maximum acid output after pentagastrin stimulation is about 70% after 24 hours of omeprazole administration.
Oral administration of omeprazole at a dose of 20 mg in patients with duodenal ulcer disease maintains gastric pH ≥ 3 for an average of 17 hours per day.
As a result of reduced gastric acid secretion and reduced gastric acidity, omeprazole, in a dose-dependent manner, reduces the exposure of the esophagus to acidic gastric contents in patients with gastroesophageal reflux disease.
The degree of inhibition of gastric acid secretion is related to the size of the area under the curve of omeprazole plasma concentration versus time (AUC); however, there is no relationship with the actual, instantaneous omeprazole plasma concentration.
No tachyphylaxis has been observed during omeprazole treatment.
Effect on Helicobacter pylori
In gastric and duodenal ulcer disease, infection with Helicobacter pylori bacteria is often present, which is the main cause of gastritis. Helicobacter pylori infection, along with gastric juice, are the main factors causing ulcer disease. It is also believed that Helicobacter pylori infection is one of the main factors causing atrophic gastritis, which is associated with an increased risk of gastric cancer.
Eradiation of H. pylori using omeprazole and antibacterial drugs results in a high percentage of cures and long-term remission of ulcer disease.
It has been found that two-component therapies are less effective than three-component therapies. However, they can be used when hypersensitivity excludes the use of a three-component regimen.
Effect on other processes related to reduced gastric acid secretion
During long-term treatment with omeprazole, the frequency of gastric glandular cysts increases. They occur as a result of inhibition of gastric acid secretion. They are benign and probably resolve spontaneously.
Reduced gastric acidity caused by various factors, including proton pump inhibitors, increases the number of bacteria normally present in the gastrointestinal tract.
Treatment with acid-suppressing drugs may lead to a slightly increased risk of gastrointestinal infections, e.g., with Salmonella or Campylobacter bacteria.
During treatment with anti-secretory drugs, serum gastrin concentration increases in response to reduced gastric acid secretion. The CgA concentration also increases due to decreased intragastric acidity. The increase in CgA concentration may interfere with tests for neuroendocrine tumors.
Available published evidence suggests that treatment with proton pump inhibitors should be discontinued 5 days to 2 weeks before measuring CgA concentration. This is to allow the CgA concentration, falsely increased by proton pump inhibitor treatment, to return to the reference range.
Children and adolescents
In an uncontrolled study in children (aged 1 to 16 years) with severe reflux esophagitis, omeprazole at doses of 0.7 to 1.4 mg/kg improved the condition in 90% of cases and also significantly reduced reflux symptoms. In a single-blind study, children aged 0 to 24 months with clinically diagnosed gastroesophageal reflux disease were treated with omeprazole doses of 0.5, 1.0, or 1.5 mg/kg body weight. The frequency of vomiting and/or regurgitation decreased by 50% after 8 weeks of treatment, regardless of dose.
Eradiation of H. pylori in children
In a randomized, double-blind clinical trial (the Héliot study), the efficacy and safety of omeprazole administered in combination with two antibiotics (amoxicillin and clarithromycin) were demonstrated in the treatment of Helicobacter pylori infections in children aged 4 years and older with gastritis: Helicobacter pylori eradication rate: 74.2% (23/31 patients) for the omeprazole + amoxicillin + clarithromycin combination, compared to 9.4% (3/32 patients) for the amoxicillin + clarithromycin combination. However, there was no evidence of clinical benefits regarding symptoms of dyspepsia. This study does not provide information on children under 4 years of age.

5.2 Pharmacokinetic properties

Absorption
Omeprazole is not stable in an acidic environment and is therefore administered orally in the form of capsules filled with enteric-coated pellets.
Omeprazole is rapidly absorbed and reaches maximum plasma concentration within approximately 1 to 2 hours after administration. Omeprazole is absorbed in the small intestine, usually within 3 to 6 hours.
Concomitant food intake does not affect the bioavailability of omeprazole. The bioavailability of omeprazole after single oral administration is approximately 40%. Multiple daily administration increases bioavailability to approximately 60%.
Distribution
The volume of distribution in healthy subjects is approximately 0.3 L/kg body weight. Omeprazole is bound to plasma proteins at approximately 97%.
Metabolism
Omeprazole is completely metabolized by the cytochrome P450 system (CYP), mainly through the polymorphic form of the CYP2C19 isoenzyme, which results in the formation of the main metabolite present in plasma - hydroxyomeprazole. The remaining part depends on another specific isoenzyme - CYP3A4, responsible for the formation of omeprazole sulfone.
Due to the high affinity of omeprazole for CYP2C19, there is a potential risk of competitive inhibition and metabolic interactions with other CYP2C19 substrates. However, due to the low affinity for CYP3A4, omeprazole does not inhibit the metabolism of other CYP3A4 substrates or major CYP isoenzymes.
In about 3% of the Caucasian population and 15-20% of the Asian population, the CYP2C19 isoenzyme with normal activity is not present. These are slow metabolizers of drugs, in whom omeprazole metabolism probably occurs through CYP3A4. After multiple administration of 20 mg omeprazole per day, the mean area under the curve of plasma concentration versus time (AUC) was 5 to 10 times higher in slow metabolizers than in subjects with normal CYP2C19 enzyme activity (rapid metabolizers). Mean plasma concentrations were also 3 to 5 times higher. These data have no implications for omeprazole dosing.
Elimination
The elimination half-life from plasma is usually less than 1 hour after both single and repeated daily administration. Omeprazole is completely eliminated from plasma between doses. No accumulation of the product has been observed during once-daily administration. Almost 80% of the orally administered dose is excreted in the urine as metabolites.
The remaining part is excreted in the feces, mainly with bile.
The total area under the curve of omeprazole plasma concentration versus time (AUC) increases after multiple administration of the product. This phenomenon is dose-dependent and non-linear. This dose and time dependence is due to the reduced first-pass effect and decreased systemic clearance, probably caused by inhibition of CYP2C19 enzyme activity by omeprazole and/or its metabolites (e.g., sulfone).
None of the metabolites affect gastric acid secretion.
Special patient groups
Patient with impaired hepatic function
In patients with liver failure, omeprazole metabolism is slowed, resulting in increased AUC. Omeprazole does not show a tendency to accumulate when administered once daily.
Patient with impaired renal function
The pharmacokinetics of omeprazole, including bioavailability and elimination rate, are not affected in patients with impaired renal function.
Elderly patients
In elderly patients (75-79 years), omeprazole metabolism is slightly slowed.
Children
When using recommended doses in children over 1 year of age, observed plasma concentrations were similar to those in adults. In children under 6 months of age, omeprazole clearance is low due to low ability to metabolize omeprazole.

5.3 Preclinical safety data

In rats, long-term studies with omeprazole have shown hyperplasia and signs of carcinoid tumors in the stomach. This was due to prolonged increased gastrin levels, secondary to inhibition of gastric acid secretion. Similar effects have been observed after treatment with H2 receptor antagonists, other proton pump inhibitors, and after partial gastrectomy. It appears that the changes in ECL cells in the stomach are not dependent on the specific drug used.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

sucrose, pellets (sucrose, corn starch),
povidone K30,
sodium lauryl sulfate,
sodium carboxymethylcellulose (type A),
disodium phosphate dodecahydrate,
hypromellose 6 cP,
triethyl citrate,
methacrylic acid and ethyl acrylate copolymer 1:1,
sodium hydroxide,
titanium dioxide (E 171),
talc
Composition of the gelatin capsule:
Capsule cap:
gelatin,
erythrosine (E 127),
indigo carmine (E 132),
titanium dioxide (E 171),
purified water.
Capsule body:
gelatin,
erythrosine (E 127),
quinoline yellow (E 104),
titanium dioxide (E 171),
purified water.
Ink:
shellac,
propylene glycol,
povidone,
sodium hydroxide,
titanium dioxide (E 171).

6.2 Incompatibilities

None.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Store at a temperature below 30°C.

6.5 Nature and contents of container

Blister pack of PA/Aluminum/PVC/Aluminum foil in a cardboard box.
Single unit package contains 7, 14, 28, or 56 capsules.
Not all pack sizes may be marketed.

6.6 Special precautions for disposal and preparation of the medicinal product for administration

None.

7. MARKETING AUTHORISATION HOLDER

RESPONSIBLE FOR BATCH RELEASE

Adamed Pharma S.A.
Pieńków, ul. M. Adamkiewicza 6A

• 05 – 152 Czosnów

8. MARKETING AUTHORISATION NUMBER

22182

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

Date of first authorisation: 07.11.2014

10. DATE OF REVISION OF THE PRODUCT INFORMATION

OR PARTIAL REVISION