OMEZ

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT OMEZ® (OMEZ)

Composition:

Active substance: omeprazole;

1 capsule contains omeprazole 10 mg;

Excipients: mannitol (E 421), crospovidone, poloxamer, hydroxypropylmethylcellulose, meglumine, povidone, methacrylic acid copolymer (type C), triethyl citrate, magnesium stearate.

Pharmaceutical form. Capsules.

Main physicochemical characteristics: nearly white to light-yellow pellets of elliptical and/or spherical shape, contained in an opaque hard gelatin capsule size "3" with a lavender-colored cap and a yellow body, marked with black print "OMEZ 10" on both the cap and the body of the capsule.

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

ATC code A02BC01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Omeprazole, a racemic mixture of two enantiomers, reduces gastric acid secretion through a targeted mechanism of action. It is a specific inhibitor of the gastric proton pump in parietal cells. It acts rapidly and provides controlled, reversible inhibition of gastric acid secretion with once-daily dosing.

Omeprazole is a weak base that accumulates and is converted into its active form in the acidic environment of intracellular canaliculi of parietal cells, where it inhibits the H⁺K⁺ATPase enzyme – the acid pump. This effect on the final stage of gastric acid production is dose-dependent and results in highly effective suppression of both basal and stimulated acid secretion, regardless of the nature of the stimulus.

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

Effect on gastric acid secretion.

Oral administration of 20 mg omeprazole once daily leads to rapid and effective inhibition of daytime and nighttime gastric acid secretion, with maximum effect achieved within 4 days of treatment. In patients with duodenal ulcer, mean reduction in gastric acidity is approximately 80% over 24 hours after administration of 20 mg omeprazole; mean reduction in peak acid output following pentagastrin stimulation is about 70% at 24 hours after omeprazole intake.

Oral administration of 20 mg omeprazole maintains intragastric pH ≥3 for a mean duration of 17 hours out of 24 in patients with duodenal ulcer. Due to reduced acid secretion and intragastric acidity, in a dose-dependent manner, omeprazole reduces/normalizes acid exposure of the esophagus in patients with gastroesophageal reflux disease. Inhibition of acid secretion correlates with the area under the plasma concentration–time curve (AUC) of omeprazole, rather than with actual plasma concentration at a given time.

No tachyphylaxis has been observed during omeprazole treatment.

Effect on H. pylori.

Peptic ulcer is associated with H. pylori, including duodenal and gastric ulcers. H. pylori is considered the primary causative factor in the development of gastritis. H. pylori and gastric acid are the main factors in the pathogenesis of peptic ulcer disease. H. pylori is the primary factor in the development of atrophic gastritis, which is associated with an increased risk of gastric cancer.

Reduction of gastric pH with omeprazole in combination with antimicrobial agents is associated with rapid symptom relief, high healing rates of mucosal lesions, and long-term remission of peptic ulcer disease.

Other effects related to acid suppression.

During long-term treatment, a slightly increased frequency of gastric foveolar (microcystic) changes has been reported. These changes are a physiological consequence of sustained acid secretion inhibition, are benign, and appear to be reversible.

Reduction of 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, for example, those caused by Salmonella and Campylobacter.

Pediatric use.

In an uncontrolled study involving children (aged 1 to 16 years) with severe erosive esophagitis, omeprazole at doses of 0.7–1.4 mg/kg improved esophagitis in 90% of cases and significantly reduced reflux symptoms. In a blinded, comparator-free study, infants and toddlers aged 0 to 24 months diagnosed with gastroesophageal reflux disease were treated with omeprazole at doses of 0.5 mg/kg, 1.0 mg/kg, and 1.5 mg/kg. The frequency of vomiting/regurgitation episodes decreased by 50% after 8 weeks of treatment, regardless of dose.

Eradication of H. pylori in children.

In a randomized, double-blind clinical trial (the Héliot study), it was concluded that omeprazole in combination with two antibiotics (amoxicillin and clarithromycin) was safe and effective in treating H. pylori infection in children aged 4 years and older with gastritis: H. pylori eradication rate was 74.2% (23/31 patients) in the omeprazole + amoxicillin + clarithromycin group, compared to 9.4% (3/32 patients) in the amoxicillin + clarithromycin group. However, no clinical benefit regarding dyspeptic symptoms was demonstrated. This study does not provide information on children under 4 years of age.

Pharmacokinetics.

Absorption. Omeprazole is rapidly absorbed, with peak plasma concentrations reached approximately 1–2 hours after dose administration. Absorption of omeprazole occurs in the small intestine and is usually complete within 3–6 hours. Concomitant food intake has no effect on bioavailability. Systemic availability (bioavailability) of omeprazole from a single oral dose is approximately 40%. After repeated once-daily administration, bioavailability increases to approximately 60%.

Distribution. The apparent volume of distribution in healthy individuals is approximately 0.3 L/kg body weight. Plasma protein binding of omeprazole is 97%.

Metabolism. Omeprazole is completely metabolized by the cytochrome P450 system. The majority of omeprazole metabolism is dependent on CYP2C19, which is responsible for the formation of hydroxyomeprazole, the main metabolite in plasma. The remaining portion is metabolized by another specific isoenzyme, CYP3A4, responsible for the formation of omeprazole sulfone. Due to the high affinity of omeprazole for CYP2C19, there is potential for competitive inhibition and metabolic interactions between omeprazole and other drugs that are CYP2C19 substrates. However, due to low affinity for CYP3A4, omeprazole has no potential to inhibit the metabolism of other CYP3A4 substrates. Furthermore, omeprazole does not have an inhibitory effect on major CYP enzymes.

Approximately 3% of the Caucasian population and 15–20% of Asian populations lack functional CYP2C19 enzyme. In these individuals, omeprazole metabolism is likely primarily catalyzed by CYP3A4. After repeated once-daily administration of 20 mg omeprazole, the mean AUC was 5–10 times higher in poor metabolizers compared to individuals with functional CYP2C19 (extensive metabolizers). Mean peak plasma concentrations were also 3–5 times higher. These observations have no implications for omeprazole dosing.

Elimination. The terminal elimination half-life of omeprazole in plasma is typically less than 1 hour, both after single and multiple once-daily oral doses. Omeprazole is completely cleared from plasma between doses, with no tendency for accumulation during once-daily administration. Approximately 80% of an oral dose of omeprazole is excreted in urine as metabolites, and the remainder in feces, primarily via biliary secretion.

With repeated administration, the AUC of omeprazole increases. This increase is dose-dependent and results in a non-linear relationship between dose and A游戏副本 after repeated dosing. This time- and dose-dependence is related to reduced presystemic metabolism and systemic clearance, possibly due to inhibition of the CYP2C19 enzyme by omeprazole and/or its metabolites (e.g., sulfone).

No metabolite has been found to have any effect on gastric acid secretion.

Special populations. Hepatic impairment. In patients with impaired liver function, omeprazole metabolism is altered, leading to increased AUC. Omeprazole has not shown any tendency toward accumulation with once-daily dosing.

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).

Children. Plasma concentrations similar to those in adults have been achieved in children aged 1 year and older when treated with recommended doses. In children under 6 months of age, omeprazole clearance is low due to limited capacity to metabolize omeprazole.

Clinical characteristics.

Indications. Dyspeptic syndrome associated with increased gastric juice acidity, manifested by heartburn, acid regurgitation, and epigastric pain.

Contraindications. Hypersensitivity to omeprazole, substituted benzimidazoles, or to any excipient. Omeprazole, like other proton pump inhibitors (PPIs), should not be used concomitantly with nelfinavir (see "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Effect of omeprazole on the pharmacokinetics of other medicinal products.

Medicinal products whose absorption depends on gastric pH.

Suppression of gastric secretion during treatment with omeprazole and other PPIs may reduce or increase the absorption of medicinal products whose absorption is pH-dependent. As with other agents that reduce intragastric acidity, absorption of drugs such as ketoconazole, itraconazole, and erlotinib may be decreased, 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, by 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 once daily) 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 concomitantly 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 decreased by 47% (after 24 hours) and by 30% (day 5) when clopidogrel and omeprazole were co-administered. In another study, administration of clopidogrel and omeprazole at different times did not prevent their interaction, likely due to the inhibitory effect of omeprazole on CYP2C19. Conflicting data on the clinical relevance of this pharmacokinetic/pharmacodynamic (PK/PD) interaction regarding 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 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/daily maintenance dose 75 mg) and omeprazole (80 mg once daily orally, i.e., a dose four times higher than the standard daily dose), resulting in a mean reduction of 46% in exposure to clopidogrel's active metabolite and a mean reduction of 16% in maximum inhibitory effect (ADP-induced) on platelet aggregation. The clinical significance of this interaction remains unclear. 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 phenytoin concentration monitoring is recommended during the first two weeks after initiating omeprazole treatment. If phenytoin dose adjustment has been performed, monitoring and further dose adjustments should be conducted after discontinuation of omeprazole.

Unknown mechanism.

Saquinavir.

Concomitant administration of omeprazole with saquinavir/ritonavir led to 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. Enhanced monitoring of tacrolimus concentrations and renal function (creatinine clearance) is required, and dose adjustment of tacrolimus may be necessary.

Methotrexate.

Elevated methotrexate levels have been reported in some patients when administered concomitantly with proton pump inhibitors. 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 enzymes, drugs known to inhibit the activity of CYP2C19 or CYP3A4, or both enzymes (such as clarithromycin and voriconazole), may lead to increased serum levels of omeprazole due to reduced metabolic rate. 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 requiring 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 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 serum levels of omeprazole due to accelerated metabolism.

Special precautions for use.

In patients with gastric ulcer or suspected gastric ulcer who present with any alarming symptom (e.g., significant unintentional weight loss, recurrent vomiting, dysphagia, hematemesis, or melena), malignancy should be excluded, as the use of the medicinal product may mask symptoms and delay correct diagnosis.

Concomitant use of atazanavir with proton pump inhibitors is not recommended. If co-administration of atazanavir with a proton pump inhibitor cannot be avoided, careful clinical monitoring (e.g., viral load) is recommended, along with increasing the dose of atazanavir to 400 mg with 100 mg ritonavir; the dose of omeprazole 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 therapy, potential interactions with medicinal products metabolized by 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.

In patients taking proton pump inhibitors, including omeprazole, for at least three months (in most cases, treatment lasted about one year), clinically significant hypomagnesemia may occur. Hypomagnesemia may manifest as severe symptoms such as fatigue, muscle spasms, seizures, delirium, vertigo, and ventricular arrhythmias. However, it should be noted that in some cases symptoms may be masked, delaying timely recognition of this complication. In most patients, symptoms resolve and magnesium levels normalize after magnesium supplementation and discontinuation of proton pump inhibitors.

Prolonged reduction in gastric acidity may lead to increased bacterial colonization of the gastrointestinal tract.

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

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

Some data suggest that proton pump inhibitor therapy may be associated with a small increased risk of osteoporosis-related fractures. Although a causal relationship between omeprazole/esomeprazole and osteoporotic fracture has not been established, patients at risk of progressive osteoporosis or osteoporotic fracture should be advised appropriate clinical monitoring according to current clinical guidelines for this condition.

During treatment with antisecretory agents, plasma gastrin concentration increases as a result of reduced acid secretion. Due to reduced acid secretion, chromogranin A (CgA) levels increase. Elevated CgA concentrations may interfere with diagnostic tests for neuroendocrine tumors. To avoid this interference, proton pump inhibitor therapy should be discontinued at least 5 days before measuring CgA levels. 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 proton pump inhibitor therapy.

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

As with all long-term treatments, especially when the treatment period exceeds one year, the patient should be under regular medical supervision.

Subacute cutaneous lupus erythematosus (SCLE)

Use of proton pump inhibitors may be associated with very rare cases of SCLE. If skin lesions occur, particularly in sun-exposed areas, and especially if accompanied by arthralgia, the patient should seek immediate medical attention, and the healthcare provider should consider discontinuing omeprazole. Previous treatment with a proton pump inhibitor may increase the risk of developing SCLE upon subsequent use of other proton pump inhibitors.

Risk of allergic reactions

Omeprazole may cause serious skin reactions. Symptoms may include: skin redness, blisters, rash (see section "Adverse reactions").

If a patient develops an allergic reaction, the medicinal product should be discontinued immediately and medical advice should be sought promptly.

Renal function impairment

Acute tubulointerstitial nephritis (ATIN) has been reported in patients taking omeprazole. ATIN may occur at any time during omeprazole therapy. Acute tubulointerstitial nephritis may progress to renal failure.

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

Use during pregnancy or breastfeeding. Study results indicate no negative effects on pregnancy or fetal or neonatal health. Omeprazole may be used during pregnancy if 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. It is unlikely that the medicinal product affects the ability to drive or operate machinery. Undesirable effects such as dizziness and visual disturbances may occur (see section "Adverse reactions"). If such disorders occur, patients should not drive or operate machinery.

Method of Administration and Dosage

Adults and children aged 12 years and older

The usual recommended dose is 1 or 2 capsules of Omez® once daily, corresponding to 10 mg or 20 mg of omeprazole, respectively, for 2–4 weeks depending on the severity and persistence of symptoms. If no improvement occurs within 4 weeks, or if symptoms reappear shortly after treatment, consult a physician.

It is recommended to take the capsules in the morning, preferably before a meal, without damaging the capsule (capsules must not be chewed or crushed), with a small amount of water.

For patients with swallowing difficulties and for children who can drink or swallow semi-solid food. The capsules may be opened and the contents swallowed immediately with half a glass of water, or mixed with a weakly acidic liquid such as any fruit juice or apple puree, or in unsalted water. This mixture should be taken immediately after preparation or within 30 minutes. Before administration, the mixture should be stirred and followed by half a glass of water. Milk or carbonated water must not be used.

Special patient groups

Renal impairment. Dose adjustment is not required in patients with renal impairment (see section "Pharmacokinetics").

Hepatic impairment. In patients with hepatic impairment, a daily dose of 10–20 mg is sufficient (see section "Pharmacokinetics").

Elderly patients (> 65 years of age). Dose adjustment is not required in elderly patients (see section "Pharmacokinetics").

Children. The drug is indicated for treatment of children aged 12 years and older.

Overdose. Data on omeprazole overdose in humans are very limited. In scientific literature, doses up to 560 mg of omeprazole have been described, and there have been isolated reports of single oral doses of 2400 mg 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 rate is not altered (first-order kinetics) with increasing dose. Treatment, if necessary, is symptomatic.

Adverse Reactions

The most commonly observed adverse effects are headache, abdominal pain, constipation, diarrhea, bloating, and nausea/vomiting. The adverse reactions listed below were identified during clinical trials with omeprazole or from post-marketing experience. Adverse reactions are classified according to system organ classes.

Blood and lymphatic system disorders: leukopenia, thrombocytopenia, agranulocytosis, pancytopenia.

Immune system disorders: hypersensitivity reactions, e.g., fever, angioneurotic edema, and anaphylactic reaction/shock.

Metabolism and nutrition disorders: hyponatremia, hypomagnesemia; severe hypomagnesemia may lead to hypocalcemia. Hypomagnesemia may also be associated with hypokalemia.

Psychiatric disorders: insomnia, agitation, confusion, depression, aggression, hallucinations.

Nervous system disorders: headache, dizziness, paresthesia, somnolence, taste disturbance.

Eye disorders: blurred vision.

Ear and labyrinth disorders: tinnitus, vertigo.

Respiratory, thoracic and mediastinal disorders: bronchospasm.

Gastrointestinal disorders: abdominal pain, constipation, diarrhea, bloating, nausea/vomiting, dry mouth, stomatitis, gastrointestinal candidiasis, microscopic colitis, fundic gland polyps (benign).

Hepatobiliary disorders: increased liver enzymes, hepatitis with or without jaundice, hepatic failure, encephalopathy in patients with pre-existing liver disease.

Skin and subcutaneous tissue disorders: dermatitis, pruritus, erythema, vesicles, rash, urticaria, alopecia, photosensitivity, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, subacute cutaneous lupus erythematosus (see section "Special warnings and precautions for use").

Musculoskeletal and connective tissue disorders: arthralgia, myalgia, muscle weakness, increased risk of fractures with long-term use (see section "Special warnings and precautions for use").

Renal and urinary disorders: tubulointerstitial nephritis (with possible progression to renal failure).

Reproductive system and breast disorders: gynecomastia.

General disorders and administration site conditions: discomfort, malaise, peripheral edema, increased sweating.

Pediatric population.

The safety of omeprazole has been evaluated in 310 children aged 0 to 16 years with acid-related disorders. Limited data are available from long-term safety studies in 46 children who received maintenance therapy with omeprazole for the treatment of severe erosive esophagitis for up to 749 days. The adverse reaction profile is similar to that observed in adults during both short- and long-term treatment. There are no long-term data on the effects of omeprazole treatment on sexual maturation and growth.

Shelf life. 3 years.

Storage conditions. Store in the original packaging, protected from light, in a place inaccessible to children, at a temperature not exceeding 25 °C.

Packaging. 10 capsules per blister. 1 or 3 blisters per cardboard box.

Prescription status. Over-the-counter (OTC).

Manufacturer. Dr. Reddy’s Laboratories Ltd, FTO – 3.

Manufacturer’s address and place of business. Plot Nos. 41, 42R, 45R and 46R, Bachupally and Mandal, Medchal-Malkajgiri District – 500090, Telangana, India.