OMEPRAZOLE

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT OMEPRAZOLE (OMEPRAZOLE)

Composition:

Active substance: omeprazole;

One capsule contains 20 mg of omeprazole in the form of pellets (8.5%);

Excipients: sodium hydrogen phosphate, sodium lauryl sulfate, calcium carbonate, mannitol (E 421), sucrose (sucrose), hypromellose (hydroxypropylmethylcellulose), methacrylate copolymer (type C), diethyl phthalate, titanium dioxide (E 171), talc;

Capsule shell composition: gelatin, titanium dioxide (E 171), quinoline yellow (E 104).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules size №2, cylindrical in shape with hemispherical ends; body – white, cap – yellow. The contents of the capsules are white or almost white odorless pellets.

Pharmacotherapeutic group.

Drugs for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. ATC code A02BC01.

Pharmacological Properties.

Pharmacodynamics.

Omeprazole is an anti-ulcer antisecretory agent. It readily penetrates into the parietal cells of the gastric mucosa, accumulates there, and becomes activated at acidic pH values. The active metabolite—sulfenamide—inhibits H⁺,K⁺-ATPase of the secretory membrane of parietal cells (proton pump), thereby preventing hydrogen ions from entering the gastric lumen and blocking the final stage of hydrochloric acid secretion. It dose-dependently reduces basal and stimulated secretion, total volume of gastric secretion, and pepsin output. It effectively suppresses both nocturnal and daytime production of hydrochloric acid.

Omeprazole exhibits bactericidal activity against Helicobacter pylori. Eradication of Helicobacter pylori with concomitant use of omeprazole and antibiotics enables rapid relief of symptoms, achieves a high rate of healing of damaged mucosa, and leads to sustained long-term remission, reducing the risk of gastrointestinal bleeding.

In reflux esophagitis, normalization of acid exposure in the esophagus and maintenance of intragastric pH > 4 for 24 hours, along with reduced damaging properties of gastric contents (inhibition of conversion of pepsinogen to pepsin), promotes symptom relief and complete healing of esophageal lesions (healing rate exceeds 90%). It is highly effective in treating severe and complicated forms of erosive and ulcerative esophagitis resistant to H₂-receptor histamine blockers. Long-term maintenance therapy prevents recurrence of reflux esophagitis and reduces the risk of complications.

Other effects related to acid inhibition

During long-term treatment, there have been reports of a partially increased incidence of formation of gastric glandular cysts. These changes are a consequence of pronounced inhibition of hydrochloric acid secretion and are benign and reversible in nature.

During treatment with antisecretory drugs, serum gastrin increases in response to reduced acid secretion. Chromogranin A also increases due to decreased gastric acidity. Elevated chromogranin A levels may interfere with the diagnosis of neuroendocrine tumors. Data indicate that proton pump inhibitors (PPIs) should be discontinued 5 to 14 days before chromogranin A measurements. This means that chromogranin A levels may remain elevated after PPI treatment and return to the normal range over time.

Pharmacokinetics.

After oral administration, the drug is rapidly and extensively absorbed from the gastrointestinal tract; however, bioavailability does not exceed 50–55% (first-pass effect in the liver). Plasma protein binding (to albumin and alpha₁-acid glycoprotein) is very high—95%.

After a single 20 mg dose of omeprazole, inhibition of gastric secretion begins within the first hour, reaches maximum effect within 2 hours, and lasts approximately 24 hours; the extent of effect is dose-dependent. The ability of parietal cells to produce hydrochloric acid recovers within 3–5 days after discontinuation of therapy.

The drug is metabolized in the liver to form at least 6 metabolites, which are practically devoid of antisecretory activity.

Excretion occurs mainly via the kidneys as metabolites (72–80%) and through the intestine (18–23%). The elimination half-life is 0.5–1 hour (with normal liver function) or 3 hours (in chronic liver disease).

In elderly patients, a slight increase in bioavailability and a decrease in elimination rate may occur.

Clinical Characteristics.

Indications.

Benign gastric ulcer and duodenal ulcer, including those associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs); eradication of Helicobacter pylori (as part of combination therapy with antibacterial agents); gastroesophageal reflux disease; prevention of aspiration of acidic gastric contents; Zollinger-Ellison syndrome; relief of symptoms of acid-related dyspepsia.

Contraindications.

Hypersensitivity to omeprazole, substituted benzimidazoles, or any other components of the drug. Omeprazole, like other proton pump inhibitors (PPIs), must not be taken concomitantly with nelfinavir or atazanavir.

Interaction with other medicinal products and other forms of interactions.

Effect of omeprazole on the pharmacokinetics of other medicinal products.

Medicinal products whose absorption is pH-dependent.

Suppression of gastric secretion during treatment with omeprazole and other PPIs may decrease or increase the absorption of medicinal products whose absorption depends on gastric pH. As with other agents that reduce gastric acidity, absorption of drugs such as ketoconazole, itraconazole, and erlotinib may be reduced, whereas absorption of drugs such as digoxin may be increased during omeprazole treatment. Concomitant administration of omeprazole (20 mg once daily) and digoxin in healthy volunteers increased digoxin bioavailability by 10% (in two out of ten subjects – up to 30%).

Nelfinavir, atazanavir.

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

Concomitant use of omeprazole and nelfinavir is contraindicated. Concomitant administration of omeprazole (40 mg once daily) reduced the average exposure to nelfinavir by approximately 40%, and the average exposure to its pharmacologically active metabolite M8 decreased by approximately 75–90%. This 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) and 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 a 30% reduction in atazanavir exposure compared to atazanavir 300 mg/ritonavir 100 mg once daily.

Digoxin.

Concomitant treatment with omeprazole (20 mg/day) and digoxin in healthy volunteers increased 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.

In a cross-over clinical study, clopidogrel (loading dose 300 mg, followed by 75 mg/day) was administered alone and with omeprazole (80 mg given simultaneously with clopidogrel) for 5 days. When clopidogrel and omeprazole were administered together, exposure to the active metabolite of clopidogrel decreased by 46% (day 1) and by 42% (day 5). The mean inhibition of platelet aggregation was reduced by 47% (after 24 hours) and by 30% (day 5) when clopidogrel and omeprazole were used together. In another study, administration of clopidogrel and omeprazole at different times did not prevent their interaction, likely due to omeprazole’s inhibitory effect on CYP2C19. Conflicting data regarding the clinical significance of this PK/PD interaction in terms of major cardiovascular events have been reported in observational and clinical studies.

Other medicinal products.

Absorption of posaconazole, erlotinib, ketoconazole, and itraconazole is significantly reduced; therefore, clinical efficacy may be diminished. Concomitant use of the drug 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 co-administered medicinal products that are also 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.

In healthy volunteers, a pharmacokinetic/pharmacodynamic interaction was observed between clopidogrel (loading dose 300 mg, followed by 75 mg daily) and omeprazole (80 mg/day orally, i.e., a dose four times higher than the standard daily dose), resulting in a mean 46% reduction in exposure to clopidogrel’s active metabolite and a mean 16% reduction in maximum inhibitory effect (ADP-induced) of platelet aggregation. The clinical significance of this interaction remains unknown. As a precautionary measure, concomitant use of omeprazole and clopidogrel should be avoided.

Cilostazol.

In healthy volunteers, administration of omeprazole 40 mg increased the Cmax and AUC of cilostazol by 18% and 26%, respectively, and of one of its active metabolites by 29% and 69%, respectively.

Phenytoin.

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

Unknown mechanism.

Saquinavir.

Concomitant administration of omeprazole with saquinavir/ritonavir increased plasma levels of saquinavir 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. Enhanced monitoring of tacrolimus concentrations and renal function (creatinine clearance) is required, and tacrolimus dosage should be adjusted as necessary.

Elevated methotrexate levels have been reported in some patients receiving concomitant therapy with proton pump inhibitors. If high-dose methotrexate therapy 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 enzymes, medicinal products known to inhibit the activity of CYP2C19 or CYP3A4, or both enzymes (e.g., clarithromycin and voriconazole), may lead to increased serum levels of omeprazole due to slowed metabolism. Concomitant administration of voriconazole resulted in more than a two-fold 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 of long-term treatment.

Omeprazole is partially metabolized by CYP3A4 as well, but does not inhibit this enzyme. Therefore, omeprazole does not affect the metabolism of medicinal products metabolized by CYP3A4, such as cyclosporine, lidocaine, quinidine, estradiol, erythromycin, and budesonide.

Inducers of CYP2C19 and/or CYP3A4.

Medicinal products known to induce the activity of CYP2C19 or CYP3A4, or both enzymes (e.g., rifampicin and St. John’s wort), may lead to decreased serum levels of omeprazole due to accelerated metabolism.

Special precautions for use.

In patients with gastric ulcer or suspected gastric ulcer, if alarming symptoms such as significant unintentional weight loss, frequent vomiting, dysphagia, hematemesis, or melena occur, malignancy must be ruled out, as the use of the drug may mask its symptoms and delay diagnosis.

Concomitant use of atazanavir with proton pump inhibitors is not recommended.

Omeprazole, like other acid-inhibiting agents, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered when treating patients with vitamin B12 deficiency, those at risk of reduced vitamin B12 absorption, or those with cachexia during long-term therapy. In individual cases, monitoring plasma vitamin B12 levels may be advisable.

Omeprazole is an inhibitor of CYP2C19. Potential interactions with drugs metabolized by CYP2C19, such as clopidogrel, should be considered at the beginning or end of omeprazole treatment.

The drug should not be used for longer than recommended in the treatment of chronic conditions in children.

Use of proton pump inhibitors may lead to a slight increase in the risk of gastrointestinal infections caused by pathogens such as Salmonella and Campylobacter.

The use of proton pump inhibitors, particularly at high doses and for prolonged periods (>1 year), may slightly increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other identified risk factors. Study data suggest that proton pump inhibitors may increase the overall risk of fractures 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 intake of vitamin D and calcium.

During long-term therapy, especially when treatment duration exceeds 1 year, patients should be under regular medical supervision, and laboratory monitoring of serum magnesium and calcium levels should be performed.

In patients taking proton pump inhibitors, including omeprazole, for at least 3 months, clinically significant hypomagnesemia may develop (in most cases, patients had been taking the drug for about 1 year).

After discontinuation of the drug, serum magnesium levels returned to normal. Clinical features of hypomagnesemia include increased neuromuscular excitability manifested by carpopedal spasms, motor agitation; tachycardia, cardiac arrhythmias, elevated blood pressure; and dystrophic disorders such as trophic erosions and skin ulcers. The diagnostic criterion for hypomagnesemia is a serum magnesium concentration below 1 mEq/L. Additionally, cases have been reported where hypomagnesemia led to hypocalcemia due to suppressed parathyroid hormone secretion under conditions of low magnesium levels in the body. In some patients, severe hypocalcemia and hypomagnesemia were observed, accompanied by seizure syndrome, cardiac rhythm disturbances, tetany, psychiatric disorders, and severe vomiting, leading to worsening of electrolyte imbalance.

The drug should not be used in patients with known hypersensitivity to omeprazole.

Omeprazole may cause serious skin reactions. Symptoms may include skin redness, blisters, rash. If an allergic reaction occurs, the drug should be discontinued immediately and medical help sought without delay.

During treatment with antisecretory drugs, plasma gastrin concentration increases as a result of reduced hydrochloric acid secretion. Due to decreased hydrochloric acid secretion, chromogranin A levels increase. Elevated chromogranin A levels may affect test results for detecting neuroendocrine tumors. To prevent such interference, proton pump inhibitor therapy should be discontinued at least 5 days before measuring chromogranin A levels. If chromogranin A and gastrin levels have not returned to reference values after initial measurements, testing should be repeated 14 days after discontinuation of PPI therapy.

Renal function

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

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

In case of intolerance to certain sugars, consult a physician before starting treatment with this drug.

Use during pregnancy or breastfeeding.

Epidemiological studies (in more than 1000 pregnant women with successful deliveries) have not shown any adverse effects of omeprazole on pregnancy and/or fetal/newborn health. The drug may be used during pregnancy only if, in the physician’s opinion, the expected benefit to the mother outweighs the potential risk to the fetus.

Omeprazole passes into breast milk in small amounts, but its effect on the infant is unknown. Therefore, breastfeeding should be discontinued during treatment with this medicinal product.

Ability to affect reaction speed when driving or operating machinery.

The effect of the drug on the ability to drive or operate machinery is unlikely; however, the possibility of adverse reactions such as dizziness and visual disturbances should be considered.

Method of Administration and Dosage

Administer orally before or during meals, without chewing or damaging the capsule, swallowing it with a small amount of liquid. The dosage regimen depends on the type and severity of the disease and is individually determined by a physician for each patient.

The capsule should be taken immediately after opening the individual blister. Do not store capsules outside the blister for later use.

Adults and children aged 12 years and older.

Peptic ulcer of the stomach and duodenum: daily dose – 1 capsule. The usual treatment course for duodenal ulcer is 4 weeks, for gastric ulcer – 8 weeks. If necessary, the daily dose may be increased to 2 capsules.

Treatment and prevention of gastric and duodenal ulcers, as well as gastro-duodenal erosions and dyspeptic symptoms associated with NSAID use: the recommended daily dose is 20 mg. Treatment duration is 4–8 weeks.

For eradication of H. pylori: omeprazole is prescribed at a daily dose of 40 mg (20 mg twice daily) as part of combination therapy according to approved international regimens:

• Triple therapy for duodenal ulcer: amoxicillin 1 g and clarithromycin 500 mg twice daily for 1 week; clarithromycin 250 mg and metronidazole 400 mg (or tinidazole 500 mg) twice daily for 1 week; amoxicillin 500 mg and metronidazole 400 mg three times daily for 1 week;
• Double therapy for duodenic ulcer: amoxicillin 750 mg – 1 g twice daily for 2 weeks; clarithromycin 500 mg three times daily for 2 weeks;
• Double therapy for gastric ulcer: amoxicillin 750 mg – 1 g twice daily for 2 weeks.

Gastroesophageal reflux disease (GERD): daily dose – 1 capsule, treatment duration – 4–8 weeks. For patients with reflux esophagitis resistant to treatment, 2 capsules daily are prescribed for 8 weeks.

Prevention of aspiration of acidic gastric contents: the recommended dose of omeprazole is 40 mg the evening before and 40 mg 2–6 hours before anesthesia.

Zollinger-Ellison syndrome: initial dose of omeprazole is 60 mg once daily in the morning; if necessary, the daily dose may be increased to 80–120 mg. The dose should be individually adjusted according to the patient's response. If the daily dose exceeds 80 mg, it should be divided into 2–3 doses.

Acid-dependent dyspepsia: daily dose is 10–20 mg once daily for 2–4 weeks. If symptoms persist after 4 weeks or recur rapidly, the patient's diagnosis should be re-evaluated. If a single dose of omeprazole less than 20 mg is required, a preparation with a lower content of active substance should be used.

Dose adjustment of omeprazole in elderly patients and in patients with renal impairment is not required.

For patients with hepatic impairment, the maximum daily dose of omeprazole is 20 mg.

Children. This dosage form of omeprazole should be used in children aged 5 years and older with body weight of at least 20 kg.

For reflux esophagitis: treatment duration – 4–8 weeks;

for symptomatic treatment of heartburn and regurgitation of hydrochloric acid in gastroesophageal reflux disease – 2–4 weeks. The daily dose is 20 mg; if necessary, the daily dose may be increased to 40 mg.

If a child cannot swallow the capsule, it should be opened and the contents mixed with a small amount of apple juice or yogurt (approximately 10 mL). Ensure that the child swallows the mixture immediately after preparation.

Omeprazole may be used as part of combination therapy for eradication of H. pylori in children aged 5 years and older, but such therapy should be conducted with special caution under strict medical supervision. Treatment duration is 7 days; if necessary, it may be extended up to 14 days.

Treatment regimen:

• children with body weight 30–40 kg: omeprazole 20 mg, amoxicillin 750 mg, clarithromycin 7.5 mg/kg body weight twice daily for 7 days;
• children with body weight over 40 kg: omeprazole 20 mg, amoxicillin 1 g, clarithromycin 500 mg twice daily for 7 days.

Children.

The drug is prescribed for children aged 5 years and older by a physician for the indications of reflux esophagitis, symptomatic treatment of heartburn and acid regurgitation in gastroesophageal reflux disease, and treatment of duodenal ulcer associated with H. pylori, under medical supervision.

Overdose.

Very limited data are available on the effects of omeprazole overdose in humans. Doses up to 560 mg of omeprazole have been described in the literature, and isolated reports have documented single oral doses of up to 2400 mg of omeprazole (120 times higher than the usual recommended clinical dose). Symptoms reported include nausea, vomiting, dizziness, abdominal pain, diarrhea, and headache. In isolated cases, lethargy, depression, and confusion have also been reported.

The described symptoms are transient in nature. Elimination kinetics remain unchanged (first-order kinetics) with increasing dose.

Treatment. There is no specific antidote. Poorly dialyzable. Gastric lavage is indicated, along with symptomatic and supportive therapy.

Adverse Reactions

The most commonly observed adverse effects are headache, abdominal pain, constipation, diarrhea, bloating, and nausea/vomiting.

For assessment of adverse reactions, the following frequency criteria are used: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated due to lack of data).

Eye disorders:
Rare – blurred vision, visual disturbances.

Ear and labyrinth disorders:
Uncommon – vertigo.

Respiratory system disorders:
Rare – bronchospasm.

Gastrointestinal disorders:
Common – abdominal pain, constipation, diarrhea, flatulence, nausea, vomiting;
Rare – dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis, abdominal discomfort, fundic gland polyps (benign).

Hepatobiliary disorders:
Uncommon – increased liver enzyme activity;
Rare – hepatitis, with or without jaundice;
Very rare – liver failure, encephalopathy in patients with known severe hepatic impairment.

Renal and urinary disorders:
Rare – interstitial nephritis;
Not known – tubulo interstitial nephritis (with possible progression to renal failure).

Metabolism and nutrition disorders:
Rare – hyponatremia;
Frequency not known – hypomagnesemia, hypocalcemia, hypokalemia.

Nervous system disorders:
Common – headache;
Uncommon – dizziness, paresthesia, sleep disturbances, feeling of weakness, somnolence;
Rare – taste disturbances.

Psychiatric disorders:
Uncommon – insomnia;
Rare – anxiety, mild disorientation, depression;
Very rare – aggression, hallucinations, agitation, confusion.

Blood and lymphatic system disorders:
Rare – thrombocytopenia, leukopenia;
Very rare – agranulocytosis, pancytopenia.

Immune system disorders:
Rare – hypersensitivity reactions such as fever, angioedema, and anaphylactic reaction/shock.

Skin and subcutaneous tissue disorders:
Uncommon – dermatitis, hyperemia, pruritus, rash, urticaria;
Rare – alopecia, photosensitivity;
Very rare – erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN);
Frequency not known – subacute cutaneous lupus erythematosus.

Musculoskeletal and connective tissue disorders:
Rare – arthralgia, myalgia, fracture of femur, wrist, or spine;
Very rare – muscle weakness.

Reproductive system and breast disorders:
Very rare – impotence, gynecomastia.

General disorders and administration site conditions:
Uncommon – malaise, peripheral edema;
Rare – increased sweating.

The adverse event profile observed in children is consistent with that in adults, both during short-term and long-term therapy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua .

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach and sight of children.

Packaging.

10 capsules per blister; 1, 2, 3, or 4 blisters per carton.

Prescription status.

Prescription only.

Manufacturer.

Date of last review.