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- TEZOL TEZOL General characteristics: International Nonproprietary Name: Esomeprazole; Main physical and chemical properties: TEZOL 20 mg and 40 mg: Pink, round, biconvex, enteric-coated tablets; Composition: 1 enteric-coated tablet 20 mg contains: Active substance: 22.30 mg esomeprazole magnesium trihydrate, equivalent to 20 mg esomeprazole; Excipients: Colloidal silicon dioxide, calcium carbonate, croscarmellose sodium, mannitol, anhydrous sodium carbonate, magnesium stearate, sodium lauryl sulfate, talc, microcrystalline cellulose, hypromellose, povidone, Coating agents: DR COAT-ECS (diethyl phthalate, methacrylic acid copolymer, talc, titanium dioxide (E 171)), erythrosine, titanium dioxide (E 171). Also see: Emanera - Emanera 20mg 14 capsules 1 enteric-coated tablet 40 mg contains: Active substance: 44.50 mg esomeprazole magnesium trihydrate, equivalent to 40 mg esomeprazole. Excipients: Colloidal silicon dioxide, calcium carbonate, croscarmellose sodium, mannitol, anhydrous sodium carbonate, magnesium stearate, sodium lauryl sulfate, talc, microcrystalline cellulose, hypromellose, povidone, Coating agents: DR COAT-ECS (diethyl phthalate, methacrylic acid copolymer, talc, titanium dioxide (E 171)), erythrosine, titanium dioxide (E 171). Dosage form: Enteric-coated tablets 20 mg and 40 mg. Pharmacological group: Drug that reduces gastric secretion - proton pump inhibitor. ATC code: A02BC05 Pharmacological properties: Esomeprazole is the S-isomer of omeprazole and reduces gastric acid secretion in the parietal cells of the stomach by specifically inhibiting the proton pump. The S- and R-isomers of omeprazole have similar pharmacodynamic activity. Mechanism of action Esomeprazole is a weak base that is converted to its active form in the highly acidic environment of the secretory canaliculi of the parietal cells of the gastric mucosa, where it inhibits the proton pump - the enzyme H+/K+-ATPase, and both basal and stimulated secretion of hydrochloric acid. The effect of oral administration of esomeprazole 20 mg and 40 mg appears within one hour. After five days of once-daily administration of esomeprazole 20 mg, pentagastrin-stimulated acid output is reduced by 90% when measured 6-7 hours after dosing on the fifth day. After five days of oral administration of esomeprazole 20 mg and 40 mg, the time with gastric pH above 4 was maintained for an average of 13, 17, and 24 hours. With esomeprazole 20 mg, a gastric pH above 4 was maintained for at least 8, 12, and 16 hours in 76%, 54%, and 24% of patients, respectively, while for the 40 mg dose of esomeprazole, these proportions were 97%, 92%, and 56%, respectively. Using AUC as a surrogate parameter for plasma concentration determination, a relationship was found between inhibition of acid secretion and exposure. Healing of reflux esophagitis with esomeprazole 40 mg is observed in approximately 78% after 4 weeks, and in 93% after 8 weeks of treatment. One week of treatment with esomeprazole 20 mg twice daily and appropriate antibiotics leads to successful eradication of H. pylori in approximately 90% of patients. After eradication therapy, no further antisecretory monotherapy is needed for effective ulcer healing and relief of symptoms of uncomplicated duodenal ulcer for one week. The efficacy of esomeprazole in peptic ulcer bleeding was demonstrated in a study of patients with endoscopically confirmed bleeding from peptic ulcers. During treatment with antisecretory drugs, serum gastrin increases in response to reduced acid secretion. Chromogranin A (CgA) also increases due to reduced gastric acidity. Elevated CgA levels may interfere with investigations for neuroendocrine tumors. Treatment with proton pump inhibitors should be discontinued at least 5 days before CgA measurement. If gastrin and CgA levels are not normalized after 5 days, measurements should be repeated 14 days after discontinuation of esomeprazole treatment. Increased ECL cell numbers, possibly related to increased serum gastrin levels, have been observed in both children and adults during long-term treatment with esomeprazole. The findings are not clinically significant. Gastric gland cysts have been observed with a slightly increased frequency during long-term treatment with antisecretory drugs. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign, and appear to be reversible. The use of drugs, including proton pump inhibitors, that suppress gastric acid secretion is associated with an increase in the microbial flora in the stomach, which normally exists in the gastrointestinal tract. The use of proton pump inhibitors may lead to a slight increase in the risk of gastrointestinal infections caused by Salmonella spp. and Campylobacter spp. bacteria, and in hospitalized patients, likely Clostridium difficile. Pharmacokinetic properties: Absorption. Esomeprazole is acid-labile and is administered orally in the form of gastro-resistant granules. In vivo, only a small portion of esomeprazole is converted to the R-isomer. Esomeprazole is rapidly absorbed, with peak plasma concentrations reached approximately 1-2 hours after dosing. Absolute bioavailability is 64% after a single 40 mg dose and increases to 89% with repeated once-daily dosing. For esomeprazole 20 mg, these values are 50% and 68%, respectively. Food intake delays and reduces the absorption of esomeprazole, but this does not significantly affect the effect of esomeprazole on gastric acidity. Distribution. The apparent volume of distribution at steady state in healthy subjects is approximately 0.22 L/kg body weight. Esomeprazole is 97% bound to plasma proteins. Biotransformation. Esomeprazole is metabolized by the cytochrome P450 system (CYP). The major part of esomeprazole is metabolized with the participation of the polymorphic isoenzyme CYP2C19, which is responsible for the formation of hydroxy- and desmethyl metabolites of esomeprazole. The remaining part depends on another specific isoenzyme, CYP3A4, which is responsible for the formation of sulfone of esomeprazole (the main metabolite in plasma). Elimination. The parameters below mainly reflect the pharmacokinetics in individuals with increased isoenzyme CYP2C19 activity. Total plasma clearance is approximately 17 L/h after a single dose and approximately 9 L/h after repeated dosing. The plasma elimination half-life is approximately 1.3 hours after repeated once-daily dosing. Esomeprazole is completely eliminated from plasma between doses without a tendency for accumulation when administered once daily. The main metabolites of esomeprazole do not affect gastric acid secretion. Almost 80% of the oral dose of esomeprazole is excreted as metabolites in the urine, with the remainder in the feces. Less than 1% of unchanged esomeprazole is found in the urine. Linearity/Non-linearity. The pharmacokinetics of esomeprazole have been studied at doses up to 40 mg twice daily. The area under the plasma concentration-time curve increases with repeated administration of esomeprazole. This increase is dose-dependent and leads to a dose-proportional increase in AUC after repeated dosing. The time and dose dependency is due to reduced first-pass metabolism and decreased systemic clearance, likely caused by the inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite. Patients in Special Populations. Poor Metabolizers. Approximately 2.9 ± 1.5% of the population lacks the functional CYP2C19 enzyme and are called poor metabolizers. In these individuals, esomeprazole metabolism is mainly catalyzed by CYP3A4. After repeated once-daily administration of esomeprazole 40 mg, the mean AUC was approximately 100% higher in poor metabolizers than in subjects with functional CYP2C19 enzyme (extensive metabolizers). The mean peak plasma concentration increased by approximately 60%. These findings do not affect the dosing of esomeprazole. Gender. After a single 40 mg dose of esomeprazole, the mean area under the plasma concentration-time curve is approximately 30% higher in women than in men. After repeated once-daily dosing, no gender difference is observed. These findings do not affect the dosing of esomeprazole. Hepatic Impairment. Esomeprazole metabolism may be impaired in patients with mild to moderate hepatic dysfunction. In patients with severe hepatic impairment, the rate of metabolism is reduced, leading to a twofold increase in the AUC of esomeprazole. Renal Impairment. Studies have not been conducted in patients with impaired renal function, as the kidney is responsible for the excretion of esomeprazole metabolites, but not for the elimination of the parent compound. Changes in esomeprazole metabolism are not expected in patients with impaired renal function. Elderly. Esomeprazole metabolism is not significantly altered in elderly subjects (71-80 years of age). Pediatric Population. Adolescents 12-18 years of age: After repeated dosing of esomeprazole 20 mg and 40 mg, the AUC and time to reach maximum plasma concentration (tmax) in adolescents aged 12 to 18 years were the same as for both doses of esomeprazole in adults. Indications: Adults: Gastroesophageal reflux disease (GERD): - Treatment of erosive reflux esophagitis; - Long-term maintenance treatment to prevent recurrence after healing of erosive reflux esophagitis; - Symptomatic treatment of gastroesophageal reflux disease. Gastric and duodenal ulcer disease (in combination with appropriate antibacterial therapy for Helicobacter pylori eradication): - Treatment of duodenal ulcer associated with Helicobacter pylori. - Prevention of recurrence of peptic ulcer associated with Helicobacter pylori. Patients on long-term NSAID therapy: - Healing of gastric ulcers associated with NSAID use; - Prevention of gastric and duodenal ulcers associated with NSAID use in patients at risk. Zollinger-Ellison syndrome. Dosage and administration: Dosage. Adults: Gastroesophageal reflux disease (GERD). Treatment of erosive reflux esophagitis: 20 mg twice daily for 4 weeks. An additional 4-week course of treatment is recommended in cases where esophagitis is not healed after the first course or symptoms persist. Long-term maintenance treatment to prevent recurrence after healing of erosive reflux esophagitis: 20 mg once daily. Symptomatic treatment of gastroesophageal reflux disease: 20 mg once daily - in patients without esophagitis. If symptoms do not resolve after 4 weeks of treatment, further investigation of the patient should be conducted. After resolution of symptoms, a switch to on-demand administration of the drug may be considered. This treatment regimen is not recommended for patients taking NSAIDs who are at risk of developing gastric or duodenal ulcers. For eradication of Helicobacter pylori in combination with appropriate antibacterial therapy. - Healing of duodenal ulcer associated with Helicobacter pylori, - Prevention of recurrence of peptic ulcers in patients with Helicobacter pylori-associated ulcers. TEZOL 20 mg together with 1 g amoxicillin and 500 mg clarithromycin, all twice daily for 7 days. Patients requiring long-term NSAID therapy. Healing of gastric ulcers associated with NSAID therapy: The usual dose is TEZOL 20 mg once daily. Duration of treatment is 4-8 weeks. Prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk: TEZOL 20 mg once daily. Treatment of Zollinger-Ellison syndrome. The recommended starting dose is TEZOL 40 mg twice daily. Dosage is subsequently adjusted individually, and treatment should be continued as clinically indicated. Based on available clinical data, most patients can be controlled with TEZOL doses of 80–160 mg per day. Daily doses above 80 mg should be divided and administered twice daily. Special Populations. Pediatric Population. Adolescents aged 12 years and older: Gastroesophageal reflux disease (GERD): - Treatment of erosive reflux esophagitis - 40 mg once daily for 4 weeks. An additional 4-week treatment is recommended for patients in whom esophagitis has not healed or who have persistent symptoms. - Long-term management of patients with healed esophagitis to prevent recurrence - 20 mg once daily. - Symptomatic treatment of gastroesophageal reflux disease (GERD). Symptomatic treatment of gastroesophageal reflux disease without esophagitis - 20 mg once daily. If symptom control is not achieved after 4 weeks, the patient should undergo further investigation. After resolution of symptoms, further symptom control may be achieved by taking TEZOL 20 mg once daily. Treatment of duodenal ulcer caused by Helicobacter pylori: When choosing an appropriate combination therapy, attention should be paid to official national, regional, and local guidelines on bacterial resistance, duration of treatment (most often 7 days, but sometimes up to 14 days), and appropriate use of antibacterial agents. Treatment should be supervised by a specialist. Dosage recommendation is: Dosage for body weight 30 - 40 kg: Combination with two antibiotics: TEZOL 20 mg, amoxicillin 750 mg, and clarithromycin 7.5 mg/kg body weight, administered simultaneously twice daily for one week. For body weight > 40 kg: Combination with two antibiotics: TEZOL 20 mg, amoxicillin 1 g, and clarithromycin 500 mg, all administered together twice daily for one week. Children under 12 years of age: TEZOL should not be used in children under 12 years of age. More appropriate pharmaceutical forms of esomeprazole may be available. Patients with Impaired Renal Function. Dose adjustment is not required in patients with impaired renal function. In patients with severe renal impairment, it is administered with caution due to limited experience. Patients with Impaired Hepatic Function. Dose adjustment is not required in patients with mild to moderate hepatic impairment. For patients with severe hepatic impairment, the maximum dose of TEZOL should not exceed 20 mg. Elderly. Dose adjustment is not required in the elderly. Method of administration. The tablets should be swallowed whole with liquid. The tablets should not be chewed or broken. For patients who have difficulty swallowing, the tablets are dissolved in half a glass of non-carbonated water until dissolved. Other liquids should not be used as they may disrupt the enteric coating. Stir until the tablets dissolve and drink the liquid with the granules immediately or within 30 minutes. Rinse the glass with half a glass of water and drink. The granules should not be chewed or crushed. For patients who cannot swallow, the tablets are dissolved in half a glass of non-carbonated water and administered via a gastric tube. It is important that the compatibility of the selected syringe and tube is carefully checked. Side effects: Summary of the safety profile. Headache, abdominal pain, diarrhea, and nausea are among the most frequently reported adverse reactions in clinical trials (and also in post-marketing use). In addition, the safety profile is similar across different formulations, indications, age groups, and patient populations. Dose-dependent adverse reactions have not been observed. Table of adverse reactions: The following adverse reactions have been identified or are suspected in the clinical trial program of TEZOL and in post-marketing studies. None were found to be dose-dependent. Reactions are classified by frequency (Very common: ≥1/10; Common: ≥1/100 to <1/10; Uncommon: ≥1/1,000 to <1/100; Rare: ≥1/10,000 to <1/1,000; Very rare <1/10,000; Unknown (cannot be estimated from available data)). Organ system class Frequency Adverse effects Disorders of the blood and lymphatic system Rare Leukopenia, thrombocytopenia Very rare Agranulocytosis, pancytopenia Disorders of the immune system Rare Hypersensitivity reactions, e.g., fever, angioneurotic edema, and anaphylactic reaction/shock Metabolic and nutritional disorders Uncommon Peripheral edema Rare Hyponatremia Unknown Hypomagnesemia; severe hypomagnesemia may be associated with hypocalcemia. Hypomagnesemia may also be associated with hypokalemia. Psychiatric disorders Uncommon Insomnia Rare Agitation, confusion, depression Very rare Aggression, hallucinations Nervous system disorders Common Headache Uncommon Dizziness, paresthesia, somnolence Rare Taste disturbance Eye disorders Rare Blurred vision Ear and labyrinth disorders Uncommon Vertigo Respiratory, thoracic and mediastinal disorders Rare Bronchospasm Gastrointestinal disorders Common Abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting, fundic gland polyps (benign) Uncommon Dry mouth Rare Stomatitis, gastrointestinal candidiasis Unknown Microscopic colitis Hepatobiliary disorders Uncommon Increased liver enzymes Rare Hepatitis with or without jaundice Very rare Hepatic failure, encephalopathy in patients with pre-existing liver disease Skin and subcutaneous tissue disorders Uncommon Dermatitis, pruritus, rash, urticaria Rare Alopecia, photosensitivity Very rare Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN) Unknown Subacute cutaneous lupus erythematosus Musculoskeletal and connective tissue disorders Uncommon Hip, wrist, or spine fracture Rare Arthralgia, myalgia Very rare Muscle weakness Renal and urinary disorders Very rare Interstitial nephritis; in some patients, renal failure was observed concurrently Reproductive system and breast disorders Very rare Gynecomastia General disorders and administration site conditions Rare Malaise, increased sweating Contraindications: Hypersensitivity to TEZOL, substituted benzimidazoles, or any of the other ingredients in the preparation. TEZOL must not be used with nelfinavir. Interactions with medicinal products and other types of interactions: Effect of TEZOL on the pharmacokinetics of other drugs. Protease inhibitors: Omeprazole is known to interact with some protease inhibitors. The clinical significance and mechanisms of these interactions are not always known. Increased gastric pH during omeprazole treatment may alter the absorption of protease inhibitors. Other possible interaction mechanisms include inhibition of CYP 2C19. In the case of atazanavir and nelfinavir, a decrease in serum levels was observed when taken with omeprazole, therefore concomitant use is not recommended. Co-administration of omeprazole (40 mg once daily) with 300 mg atazanavir / 100 mg ritonavir in healthy volunteers resulted in a significant reduction in atazanavir exposure (75% reduction in AUC, Cmax, and Cmin). Increasing the dose of atazanavir to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Co-administration of omeprazole (20 mg daily) with 400 mg atazanavir / 100 mg ritonavir in healthy volunteers resulted in a reduction in atazanavir exposure by approximately 30% compared to the exposure observed with daily administration of 300 mg atazanavir / 100 mg ritonavir without 20 mg omeprazole. Co-administration of omeprazole (40 mg daily) reduced the mean AUC, Cmax, and Cmin of nelfinavir by 36-39%, and the mean AUC, Cmax, and Cmin of the pharmacologically active metabolite M8 were reduced by 75-92%. Due to the pharmacodynamic effects and pharmacokinetic properties of TEZOL and TEZOL-like drugs, concomitant administration of TEZOL and atazanavir is not recommended, and concomitant administration of TEZOL and nelfinavir is contraindicated. With saquinavir (when taken with ritonavir), an increase in serum levels (80-100%) was observed during concomitant treatment with omeprazole (40 mg daily). Treatment with omeprazole 20 mg daily does not affect the exposure of darunavir (with concomitant ritonavir) and amprenavir (with concomitant ritonavir). Treatment with TEZOL 20 mg daily does not affect the exposure of amprenavir (with or without concomitant ritonavir). Treatment with omeprazole 40 mg daily does not affect the exposure of lopinavir (with concomitant ritonavir). Methotrexate: Increased levels of methotrexate have been reported in some patients when taken with PPIs. With high-dose methotrexate, temporary withdrawal of TEZOL may be necessary. Tacrolimus: Concomitant administration of TEZOL increases tacrolimus levels in serum. Enhanced monitoring of tacrolimus concentrations, as well as renal function (creatinine clearance), should be performed, and tacrolimus dosage adjustment should be made if necessary. Medicinal products with pH-dependent absorption: Inhibition of gastric acid by TEZOL and other PPIs may decrease or increase the absorption of medicinal products whose absorption is pH-dependent. As with other acid-reducing agents, the absorption of medicinal products such as ketoconazole, itraconazole, and erlotinib may be reduced during TEZOL treatment, while the absorption of digoxin may be increased. Concomitant treatment with TEZOL (20 mg daily) and digoxin in healthy volunteers increased the bioavailability of digoxin by 10% (up to 30% in two out of ten). Digoxin toxicity is rarely observed. Caution is advised when prescribing high doses of TEZOL in elderly patients; enhanced therapeutic monitoring of digoxin is necessary. Medicinal products metabolized by CYP2C19: TEZOL inhibits CYP2C19, the main enzyme metabolizing TEZOL. Thus, when TEZOL is combined with drugs metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., it may lead to increased plasma concentrations of these drugs and require dose reduction. This is particularly important to consider when TEZOL therapy is necessary. Diazepam: Co-administration of TEZOL 30 mg resulted in a 45% reduction in the clearance of diazepam, a CYP2C19 substrate. Phenytoin: Co-administration of TEZOL 40 mg in epileptic patients resulted in a 13% increase in phenytoin concentration in plasma. Monitoring of phenytoin concentrations in plasma is recommended when initiating or discontinuing TEZOL treatment. Voriconazole: Omeprazole (40 mg once daily) increased the Cmax and AUCτ of voriconazole (a CYP2C19 substrate) by 15% and 41%, respectively. Cilostazol: Omeprazole, like TEZOL, acts as a CYP2C19 inhibitor. In a crossover study in healthy volunteers, omeprazole at a dose of 40 mg increased the Cmax and AUC of cilostazol by 18% and 26%, respectively, and those of one of its active metabolites by 29% and 69%, respectively. Warfarin: A clinical study showed that co-administration of TEZOL 40 mg with patients taking warfarin resulted in coagulation times within acceptable limits. However, several cases of clinically significant increases in INR have been reported in post-marketing surveillance. Monitoring is recommended when initiating and completing treatment with TEZOL in patients treated with warfarin or other coumarin derivatives. Cisapride: In healthy volunteers, co-administration of TEZOL 40 mg resulted in a 32% increase in the area under the plasma concentration/time curve (AUC) and a 31% prolongation of the elimination half-life (T 1/2 ), but peak plasma concentrations were not significantly changed. Following cisapride administration, a slight prolongation of the QTc interval was observed, but no further prolongation occurred with concomitant use with TEZOL. Clopidogrel: Studies in healthy subjects have shown a pharmacokinetic (PK)/pharmacodynamic (PD) interaction between clopidogrel (300 mg loading dose / 75 mg daily maintenance dose) and TEZOL (40 mg daily), leading to a mean reduction in exposure to the active metabolite of clopidogrel by 40% and a mean reduction in the maximum inhibition of platelet aggregation (ADP-induced) by 14%. In a study in healthy subjects, when clopidogrel was administered with a fixed combination dose of TEZOL 20 mg + ASA 81 mg, the exposure to the active metabolite of clopidogrel was reduced by almost 40% compared to administration of clopidogrel alone. However, the maximum level of ADP-induced platelet aggregation in these subjects was similar in the clopidogrel group and the clopidogrel + combination (TEZOL+ASA) product group. Both observational and clinical studies have yielded conflicting data on the clinical outcomes of TEZOL PK/PD interactions regarding cardiovascular events. Due to caution, concomitant administration of clopidogrel is not recommended. Investigated drugs without clinically significant interactions. Amoxicillin and quinidine: Esomeprazole has been shown to have no clinically significant effect on the pharmacokinetics of amoxicillin or quinidine. Naproxen or rofecoxib: Studies evaluating the co-administration of TEZOL with naproxen or rofecoxib did not reveal any clinically significant pharmacokinetic interactions during short-term studies. Medicinal products that inhibit CYP2C19 and/or CYP3A4: TEZOL is metabolized by CYP2C19 and CYP3A4. Co-administration of TEZOL with CYP3A4 inhibitor, clarithromycin (500 mg once daily), resulted in a twofold increase in TEZOL exposure (AUC). Concomitant administration of TEZOL with a combined inhibitor of CYP2C19 and CYP3A4 may lead to a twofold increase in TEZOL exposure. Voriconazole, a CYP2C19 and CYP3A4 inhibitor, increased the AUCτ of omeprazole by 280%. Dose adjustment of TEZOL is not routinely required in any of these cases. However, dose adjustment should be considered in patients with severe hepatic impairment and for long-term indications. Medicinal products that induce CYP2C19 and/or CYP3A4: Drugs known to induce CYP2C19 or CYP3A4, or both (e.g., rifampicin and St. John's wort), may lead to reduced serum levels of TEZOL due to increased metabolism of TEZOL. Pediatric Population. Interaction studies have only been conducted in adults. Overdose: To date, experience with intentional overdose is very limited. Symptoms associated with 280 mg included gastrointestinal symptoms and weakness. A single dose of 80 mg TEZOL did not cause complications. No specific antidote is known. TEZOL is highly protein-bound and therefore not readily dialyzable. As with any overdose, treatment is symptomatic along with general supportive measures. Pregnancy and lactation: Pregnancy. Clinical data on pregnancy with TEZOL exposure are insufficient. Epidemiological study data from observations of a large number of pregnancies using the racemic mixture of omeprazole did not reveal fetotoxicity or developmental defects. Animal studies have not revealed direct or indirect harmful effects of TEZOL on embryonic/fetal development. Animal studies with the racemic mixture have not revealed direct or indirect harmful effects on pregnancy, childbirth, or the postnatal development period. Caution is advised when prescribing to pregnant women. A moderate number of data in pregnant women (300-1000 pregnancy outcomes) do not indicate malformative or feto/neonatal toxicity of TEZOL. Animal studies have not shown direct or indirect harmful effects regarding reproductive toxicity. Lactation. It is unknown whether TEZOL is excreted in human breast milk. Information on the effect of TEZOL on newborns/infants is insufficient. TEZOL should not be used during lactation. Fertility. Animal studies with oral administration of the racemic mixture of omeprazole did not indicate an effect on fertility. Special precautions: In the presence of any alarming symptoms (e.g., significant unintentional weight loss, recurrent vomiting, dysphagia, hematemesis or melena) and in case of suspected or existing gastric ulcer, malignancy should be excluded, as treatment with TEZOL may mask symptoms and delay diagnosis. Long-term use. Patients on long-term treatment (especially for more than one year) should be under regular supervision. Helicobacter pylori eradication. When prescribing TEZOL for Helicobacter pylori eradication, potential drug interactions of all components of triple therapy should be considered. Clarithromycin is a potent inhibitor of CYP3A4 and therefore contraindications and interactions of clarithromycin should be considered when triple therapy is used in patients concomitantly taking drugs metabolized by CYP3A4, such as cisapride. Gastrointestinal infections. Treatment with proton pump inhibitors may lead to a slightly increased risk of gastrointestinal infections, such as Salmonella and Campylobacter. Vitamin B12 absorption. TEZOL, like other acid-blocking drugs, may reduce vitamin B12 (cyanocobalamin) absorption due to hypo- or achlorhydria. This should be considered for long-term therapy in patients with reduced vitamin B12 stores or risk factors for impaired absorption of vitamin B12. Hypomagnesemia. Severe hypomagnesemia has been reported in patients treated with proton pump inhibitors (PPIs), such as TEZOL, for at least three months and in most cases for one year. Serious manifestations of hypomagnesemia, such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia, may be asymptomatic and go unnoticed. In most cases, hypomagnesemia improved after replacement therapy with magnesium preparations and discontinuation of PPIs. In patients on long-term treatment or who take PPIs with digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), magnesium levels should be measured before initiating PPI treatment and periodically during treatment. Fracture risk. Proton pump inhibitors, especially at high doses and for long-term use (more than 1 year), may slightly increase the risk of hip, wrist, and spine fractures, mainly in elderly patients or in the presence of other known risk factors. According to observational studies, proton pump inhibitors may increase the overall risk of fractures by 10-40%. This increase may be related to other risk factors. Patients at risk of osteoporosis should receive treatment according to current clinical guidelines and should receive adequate vitamin D and calcium. Subcutaneous lupus erythematosus (SCLE). Proton pump inhibitors have been associated with very rare cases of SCLE. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, TEZOL administration should be discontinued. Previous treatment with proton pump inhibitors may increase the risk of SCLE to other proton pump inhibitors. Combination with other medicinal products. Concomitant administration of TEZOL with atazanavir is not recommended. If combination of atazanavir with a proton pump inhibitor is unavoidable, careful clinical monitoring is recommended with an increase in atazanavir dose to 400 mg with 100 mg ritonavir; the dose of TEZOL should not exceed 20 mg. TEZOL is a CYP2C19 inhibitor. When initiating or discontinuing TEZOL treatment, potential interactions with drugs metabolized by CYP2C19 should be considered. An interaction between clopidogrel and TEZOL has been established. The clinical significance of this interaction is unknown. Due to caution, concomitant administration of TEZOL and clopidogrel should be discontinued. When initiating TEZOL therapy on an as-needed basis, the consequences of interactions with other pharmaceutical agents due to fluctuations in TEZOL plasma concentration should be considered. Severe skin reactions (SCARs). Severe skin reactions (SCARs), such as erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening, have been reported very rarely in association with TEZOL treatment. Effect on laboratory tests. Increased levels of chromogranin A (CgA) may interfere with neuroendocrine tumor investigations. To avoid this effect, TEZOL treatment should be discontinued at least five days before CgA determination and repeated 14 days after discontinuation of PPI treatment. Sodium. This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is essentially "sodium-free". Effect of the preparation on the ability to drive and use machinery: TEZOL has a minor influence on the ability to drive or use machinery. Adverse reactions such as dizziness (uncommon) and blurred vision (rare) have been reported. If these symptoms occur, patients should not drive or operate machinery. Packaging: 10 tablets in a blister, 2 blisters in a cardboard box. Storage conditions: Store at a temperature not exceeding 25°C in the original packaging. Keep out of reach of children. Administration of the preparation is not allowed in case of any visible defects. Shelf life: 2 years. The preparation must not be used after the expiry date indicated on the packaging. Conditions of dispensing from the pharmacy: Pharmaceutical product group III, available without a prescription.
- Active
- esomeprazole
What is it?
TEZOL TEZOL General characteristics: International Nonproprietary Name: Esomeprazole; Main physical and chemical properties: TEZOL 20 mg and 40 mg: Pink, round, biconvex, enteric-coated tablets; Composition: 1 enteric-coated tablet 20 mg contains: Active substance: 22.30 mg esomeprazole magnesium trihydrate, equivalent to 20 mg esomeprazole; Excipients: Colloidal silicon dioxide, calcium carbonate, croscarmellose sodium, mannitol, anhydrous sodium carbonate, magnesium stearate, sodium lauryl sulfate, talc, microcrystalline cellulose, hypromellose, povidone, Coating agents: DR COAT-ECS (diethyl phthalate, methacrylic acid copolymer, talc, titanium dioxide (E 171)), erythrosine, titanium dioxide (E 171). Also see: Emanera - Emanera 20mg 14 capsules 1 enteric-coated tablet 40 mg contains: Active substance: 44.50 mg esomeprazole magnesium trihydrate, equivalent to 40 mg esomeprazole. Excipients: Colloidal silicon dioxide, calcium carbonate, croscarmellose sodium, mannitol, anhydrous sodium carbonate, magnesium stearate, sodium lauryl sulfate, talc, microcrystalline cellulose, hypromellose, povidone, Coating agents: DR COAT-ECS (diethyl phthalate, methacrylic acid copolymer, talc, titanium dioxide (E 171)), erythrosine, titanium dioxide (E 171). Dosage form: Enteric-coated tablets 20 mg and 40 mg. Pharmacological group: Drug that reduces gastric secretion - proton pump inhibitor. ATC code: A02BC05 Pharmacological properties: Esomeprazole is the S-isomer of omeprazole and reduces gastric acid secretion in the parietal cells of the stomach by specifically inhibiting the proton pump. The S- and R-isomers of omeprazole have similar pharmacodynamic activity. Mechanism of action Esomeprazole is a weak base that is converted to its active form in the highly acidic environment of the secretory canaliculi of the parietal cells of the gastric mucosa, where it inhibits the proton pump - the enzyme H+/K+-ATPase, and both basal and stimulated secretion of hydrochloric acid. The effect of oral administration of esomeprazole 20 mg and 40 mg appears within one hour. After five days of once-daily administration of esomeprazole 20 mg, pentagastrin-stimulated acid output is reduced by 90% when measured 6-7 hours after dosing on the fifth day. After five days of oral administration of esomeprazole 20 mg and 40 mg, the time with gastric pH above 4 was maintained for an average of 13, 17, and 24 hours. With esomeprazole 20 mg, a gastric pH above 4 was maintained for at least 8, 12, and 16 hours in 76%, 54%, and 24% of patients, respectively, while for the 40 mg dose of esomeprazole, these proportions were 97%, 92%, and 56%, respectively. Using AUC as a surrogate parameter for plasma concentration determination, a relationship was found between inhibition of acid secretion and exposure. Healing of reflux esophagitis with esomeprazole 40 mg is observed in approximately 78% after 4 weeks, and in 93% after 8 weeks of treatment. One week of treatment with esomeprazole 20 mg twice daily and appropriate antibiotics leads to successful eradication of H. pylori in approximately 90% of patients. After eradication therapy, no further antisecretory monotherapy is needed for effective ulcer healing and relief of symptoms of uncomplicated duodenal ulcer for one week. The efficacy of esomeprazole in peptic ulcer bleeding was demonstrated in a study of patients with endoscopically confirmed bleeding from peptic ulcers. During treatment with antisecretory drugs, serum gastrin increases in response to reduced acid secretion. Chromogranin A (CgA) also increases due to reduced gastric acidity. Elevated CgA levels may interfere with investigations for neuroendocrine tumors. Treatment with proton pump inhibitors should be discontinued at least 5 days before CgA measurement. If gastrin and CgA levels are not normalized after 5 days, measurements should be repeated 14 days after discontinuation of esomeprazole treatment. Increased ECL cell numbers, possibly related to increased serum gastrin levels, have been observed in both children and adults during long-term treatment with esomeprazole. The findings are not clinically significant. Gastric gland cysts have been observed with a slightly increased frequency during long-term treatment with antisecretory drugs. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign, and appear to be reversible. The use of drugs, including proton pump inhibitors, that suppress gastric acid secretion is associated with an increase in the microbial flora in the stomach, which normally exists in the gastrointestinal tract. The use of proton pump inhibitors may lead to a slight increase in the risk of gastrointestinal infections caused by Salmonella spp. and Campylobacter spp. bacteria, and in hospitalized patients, likely Clostridium difficile. Pharmacokinetic properties: Absorption. Esomeprazole is acid-labile and is administered orally in the form of gastro-resistant granules. In vivo, only a small portion of esomeprazole is converted to the R-isomer. Esomeprazole is rapidly absorbed, with peak plasma concentrations reached approximately 1-2 hours after dosing. Absolute bioavailability is 64% after a single 40 mg dose and increases to 89% with repeated once-daily dosing. For esomeprazole 20 mg, these values are 50% and 68%, respectively. Food intake delays and reduces the absorption of esomeprazole, but this does not significantly affect the effect of esomeprazole on gastric acidity. Distribution. The apparent volume of distribution at steady state in healthy subjects is approximately 0.22 L/kg body weight. Esomeprazole is 97% bound to plasma proteins. Biotransformation. Esomeprazole is metabolized by the cytochrome P450 system (CYP). The major part of esomeprazole is metabolized with the participation of the polymorphic isoenzyme CYP2C19, which is responsible for the formation of hydroxy- and desmethyl metabolites of esomeprazole. The remaining part depends on another specific isoenzyme, CYP3A4, which is responsible for the formation of sulfone of esomeprazole (the main metabolite in plasma). Elimination. The parameters below mainly reflect the pharmacokinetics in individuals with increased isoenzyme CYP2C19 activity. Total plasma clearance is approximately 17 L/h after a single dose and approximately 9 L/h after repeated dosing. The plasma elimination half-life is approximately 1.3 hours after repeated once-daily dosing. Esomeprazole is completely eliminated from plasma between doses without a tendency for accumulation when administered once daily. The main metabolites of esomeprazole do not affect gastric acid secretion. Almost 80% of the oral dose of esomeprazole is excreted as metabolites in the urine, with the remainder in the feces. Less than 1% of unchanged esomeprazole is found in the urine. Linearity/Non-linearity. The pharmacokinetics of esomeprazole have been studied at doses up to 40 mg twice daily. The area under the plasma concentration-time curve increases with repeated administration of esomeprazole. This increase is dose-dependent and leads to a dose-proportional increase in AUC after repeated dosing. The time and dose dependency is due to reduced first-pass metabolism and decreased systemic clearance, likely caused by the inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulfone metabolite. Patients in Special Populations. Poor Metabolizers. Approximately 2.9 ± 1.5% of the population lacks the functional CYP2C19 enzyme and are called poor metabolizers. In these individuals, esomeprazole metabolism is mainly catalyzed by CYP3A4. After repeated once-daily administration of esomeprazole 40 mg, the mean AUC was approximately 100% higher in poor metabolizers than in subjects with functional CYP2C19 enzyme (extensive metabolizers). The mean peak plasma concentration increased by approximately 60%. These findings do not affect the dosing of esomeprazole. Gender. After a single 40 mg dose of esomeprazole, the mean area under the plasma concentration-time curve is approximately 30% higher in women than in men. After repeated once-daily dosing, no gender difference is observed. These findings do not affect the dosing of esomeprazole. Hepatic Impairment. Esomeprazole metabolism may be impaired in patients with mild to moderate hepatic dysfunction. In patients with severe hepatic impairment, the rate of metabolism is reduced, leading to a twofold increase in the AUC of esomeprazole. Renal Impairment. Studies have not been conducted in patients with impaired renal function, as the kidney is responsible for the excretion of esomeprazole metabolites, but not for the elimination of the parent compound. Changes in esomeprazole metabolism are not expected in patients with impaired renal function. Elderly. Esomeprazole metabolism is not significantly altered in elderly subjects (71-80 years of age). Pediatric Population. Adolescents 12-18 years of age: After repeated dosing of esomeprazole 20 mg and 40 mg, the AUC and time to reach maximum plasma concentration (tmax) in adolescents aged 12 to 18 years were the same as for both doses of esomeprazole in adults. Indications: Adults: Gastroesophageal reflux disease (GERD): - Treatment of erosive reflux esophagitis; - Long-term maintenance treatment to prevent recurrence after healing of erosive reflux esophagitis; - Symptomatic treatment of gastroesophageal reflux disease. Gastric and duodenal ulcer disease (in combination with appropriate antibacterial therapy for Helicobacter pylori eradication): - Treatment of duodenal ulcer associated with Helicobacter pylori. - Prevention of recurrence of peptic ulcer associated with Helicobacter pylori. Patients on long-term NSAID therapy: - Healing of gastric ulcers associated with NSAID use; - Prevention of gastric and duodenal ulcers associated with NSAID use in patients at risk. Zollinger-Ellison syndrome. Dosage and administration: Dosage. Adults: Gastroesophageal reflux disease (GERD). Treatment of erosive reflux esophagitis: 20 mg twice daily for 4 weeks. An additional 4-week course of treatment is recommended in cases where esophagitis is not healed after the first course or symptoms persist. Long-term maintenance treatment to prevent recurrence after healing of erosive reflux esophagitis: 20 mg once daily. Symptomatic treatment of gastroesophageal reflux disease: 20 mg once daily - in patients without esophagitis. If symptoms do not resolve after 4 weeks of treatment, further investigation of the patient should be conducted. After resolution of symptoms, a switch to on-demand administration of the drug may be considered. This treatment regimen is not recommended for patients taking NSAIDs who are at risk of developing gastric or duodenal ulcers. For eradication of Helicobacter pylori in combination with appropriate antibacterial therapy. - Healing of duodenal ulcer associated with Helicobacter pylori, - Prevention of recurrence of peptic ulcers in patients with Helicobacter pylori-associated ulcers. TEZOL 20 mg together with 1 g amoxicillin and 500 mg clarithromycin, all twice daily for 7 days. Patients requiring long-term NSAID therapy. Healing of gastric ulcers associated with NSAID therapy: The usual dose is TEZOL 20 mg once daily. Duration of treatment is 4-8 weeks. Prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk: TEZOL 20 mg once daily. Treatment of Zollinger-Ellison syndrome. The recommended starting dose is TEZOL 40 mg twice daily. Dosage is subsequently adjusted individually, and treatment should be continued as clinically indicated. Based on available clinical data, most patients can be controlled with TEZOL doses of 80–160 mg per day. Daily doses above 80 mg should be divided and administered twice daily. Special Populations. Pediatric Population. Adolescents aged 12 years and older: Gastroesophageal reflux disease (GERD): - Treatment of erosive reflux esophagitis - 40 mg once daily for 4 weeks. An additional 4-week treatment is recommended for patients in whom esophagitis has not healed or who have persistent symptoms. - Long-term management of patients with healed esophagitis to prevent recurrence - 20 mg once daily. - Symptomatic treatment of gastroesophageal reflux disease (GERD). Symptomatic treatment of gastroesophageal reflux disease without esophagitis - 20 mg once daily. If symptom control is not achieved after 4 weeks, the patient should undergo further investigation. After resolution of symptoms, further symptom control may be achieved by taking TEZOL 20 mg once daily. Treatment of duodenal ulcer caused by Helicobacter pylori: When choosing an appropriate combination therapy, attention should be paid to official national, regional, and local guidelines on bacterial resistance, duration of treatment (most often 7 days, but sometimes up to 14 days), and appropriate use of antibacterial agents. Treatment should be supervised by a specialist. Dosage recommendation is: Dosage for body weight 30 - 40 kg: Combination with two antibiotics: TEZOL 20 mg, amoxicillin 750 mg, and clarithromycin 7.5 mg/kg body weight, administered simultaneously twice daily for one week. For body weight > 40 kg: Combination with two antibiotics: TEZOL 20 mg, amoxicillin 1 g, and clarithromycin 500 mg, all administered together twice daily for one week. Children under 12 years of age: TEZOL should not be used in children under 12 years of age. More appropriate pharmaceutical forms of esomeprazole may be available. Patients with Impaired Renal Function. Dose adjustment is not required in patients with impaired renal function. In patients with severe renal impairment, it is administered with caution due to limited experience. Patients with Impaired Hepatic Function. Dose adjustment is not required in patients with mild to moderate hepatic impairment. For patients with severe hepatic impairment, the maximum dose of TEZOL should not exceed 20 mg. Elderly. Dose adjustment is not required in the elderly. Method of administration. The tablets should be swallowed whole with liquid. The tablets should not be chewed or broken. For patients who have difficulty swallowing, the tablets are dissolved in half a glass of non-carbonated water until dissolved. Other liquids should not be used as they may disrupt the enteric coating. Stir until the tablets dissolve and drink the liquid with the granules immediately or within 30 minutes. Rinse the glass with half a glass of water and drink. The granules should not be chewed or crushed. For patients who cannot swallow, the tablets are dissolved in half a glass of non-carbonated water and administered via a gastric tube. It is important that the compatibility of the selected syringe and tube is carefully checked. Side effects: Summary of the safety profile. Headache, abdominal pain, diarrhea, and nausea are among the most frequently reported adverse reactions in clinical trials (and also in post-marketing use). In addition, the safety profile is similar across different formulations, indications, age groups, and patient populations. Dose-dependent adverse reactions have not been observed. Table of adverse reactions: The following adverse reactions have been identified or are suspected in the clinical trial program of TEZOL and in post-marketing studies. None were found to be dose-dependent. Reactions are classified by frequency (Very common: ≥1/10; Common: ≥1/100 to <1/10; Uncommon: ≥1/1,000 to <1/100; Rare: ≥1/10,000 to <1/1,000; Very rare <1/10,000; Unknown (cannot be estimated from available data)). Organ system class Frequency Adverse effects Disorders of the blood and lymphatic system Rare Leukopenia, thrombocytopenia Very rare Agranulocytosis, pancytopenia Disorders of the immune system Rare Hypersensitivity reactions, e.g., fever, angioneurotic edema, and anaphylactic reaction/shock Metabolic and nutritional disorders Uncommon Peripheral edema Rare Hyponatremia Unknown Hypomagnesemia; severe hypomagnesemia may be associated with hypocalcemia. Hypomagnesemia may also be associated with hypokalemia. Psychiatric disorders Uncommon Insomnia Rare Agitation, confusion, depression Very rare Aggression, hallucinations Nervous system disorders Common Headache Uncommon Dizziness, paresthesia, somnolence Rare Taste disturbance Eye disorders Rare Blurred vision Ear and labyrinth disorders Uncommon Vertigo Respiratory, thoracic and mediastinal disorders Rare Bronchospasm Gastrointestinal disorders Common Abdominal pain, constipation, diarrhea, flatulence, nausea/vomiting, fundic gland polyps (benign) Uncommon Dry mouth Rare Stomatitis, gastrointestinal candidiasis Unknown Microscopic colitis Hepatobiliary disorders Uncommon Increased liver enzymes Rare Hepatitis with or without jaundice Very rare Hepatic failure, encephalopathy in patients with pre-existing liver disease Skin and subcutaneous tissue disorders Uncommon Dermatitis, pruritus, rash, urticaria Rare Alopecia, photosensitivity Very rare Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN) Unknown Subacute cutaneous lupus erythematosus Musculoskeletal and connective tissue disorders Uncommon Hip, wrist, or spine fracture Rare Arthralgia, myalgia Very rare Muscle weakness Renal and urinary disorders Very rare Interstitial nephritis; in some patients, renal failure was observed concurrently Reproductive system and breast disorders Very rare Gynecomastia General disorders and administration site conditions Rare Malaise, increased sweating Contraindications: Hypersensitivity to TEZOL, substituted benzimidazoles, or any of the other ingredients in the preparation. TEZOL must not be used with nelfinavir. Interactions with medicinal products and other types of interactions: Effect of TEZOL on the pharmacokinetics of other drugs. Protease inhibitors: Omeprazole is known to interact with some protease inhibitors. The clinical significance and mechanisms of these interactions are not always known. Increased gastric pH during omeprazole treatment may alter the absorption of protease inhibitors. Other possible interaction mechanisms include inhibition of CYP 2C19. In the case of atazanavir and nelfinavir, a decrease in serum levels was observed when taken with omeprazole, therefore concomitant use is not recommended. Co-administration of omeprazole (40 mg once daily) with 300 mg atazanavir / 100 mg ritonavir in healthy volunteers resulted in a significant reduction in atazanavir exposure (75% reduction in AUC, Cmax, and Cmin). Increasing the dose of atazanavir to 400 mg did not compensate for the effect of omeprazole on atazanavir exposure. Co-administration of omeprazole (20 mg daily) with 400 mg atazanavir / 100 mg ritonavir in healthy volunteers resulted in a reduction in atazanavir exposure by approximately 30% compared to the exposure observed with daily administration of 300 mg atazanavir / 100 mg ritonavir without 20 mg omeprazole. Co-administration of omeprazole (40 mg daily) reduced the mean AUC, Cmax, and Cmin of nelfinavir by 36-39%, and the mean AUC, Cmax, and Cmin of the pharmacologically active metabolite M8 were reduced by 75-92%. Due to the pharmacodynamic effects and pharmacokinetic properties of TEZOL and TEZOL-like drugs, concomitant administration of TEZOL and atazanavir is not recommended, and concomitant administration of TEZOL and nelfinavir is contraindicated. With saquinavir (when taken with ritonavir), an increase in serum levels (80-100%) was observed during concomitant treatment with omeprazole (40 mg daily). Treatment with omeprazole 20 mg daily does not affect the exposure of darunavir (with concomitant ritonavir) and amprenavir (with concomitant ritonavir). Treatment with TEZOL 20 mg daily does not affect the exposure of amprenavir (with or without concomitant ritonavir). Treatment with omeprazole 40 mg daily does not affect the exposure of lopinavir (with concomitant ritonavir). Methotrexate: Increased levels of methotrexate have been reported in some patients when taken with PPIs. With high-dose methotrexate, temporary withdrawal of TEZOL may be necessary. Tacrolimus: Concomitant administration of TEZOL increases tacrolimus levels in serum. Enhanced monitoring of tacrolimus concentrations, as well as renal function (creatinine clearance), should be performed, and tacrolimus dosage adjustment should be made if necessary. Medicinal products with pH-dependent absorption: Inhibition of gastric acid by TEZOL and other PPIs may decrease or increase the absorption of medicinal products whose absorption is pH-dependent. As with other acid-reducing agents, the absorption of medicinal products such as ketoconazole, itraconazole, and erlotinib may be reduced during TEZOL treatment, while the absorption of digoxin may be increased. Concomitant treatment with TEZOL (20 mg daily) and digoxin in healthy volunteers increased the bioavailability of digoxin by 10% (up to 30% in two out of ten). Digoxin toxicity is rarely observed. Caution is advised when prescribing high doses of TEZOL in elderly patients; enhanced therapeutic monitoring of digoxin is necessary. Medicinal products metabolized by CYP2C19: TEZOL inhibits CYP2C19, the main enzyme metabolizing TEZOL. Thus, when TEZOL is combined with drugs metabolized by CYP2C19, such as diazepam, citalopram, imipramine, clomipramine, phenytoin, etc., it may lead to increased plasma concentrations of these drugs and require dose reduction. This is particularly important to consider when TEZOL therapy is necessary. Diazepam: Co-administration of TEZOL 30 mg resulted in a 45% reduction in the clearance of diazepam, a CYP2C19 substrate. Phenytoin: Co-administration of TEZOL 40 mg in epileptic patients resulted in a 13% increase in phenytoin concentration in plasma. Monitoring of phenytoin concentrations in plasma is recommended when initiating or discontinuing TEZOL treatment. Voriconazole: Omeprazole (40 mg once daily) increased the Cmax and AUCτ of voriconazole (a CYP2C19 substrate) by 15% and 41%, respectively. Cilostazol: Omeprazole, like TEZOL, acts as a CYP2C19 inhibitor. In a crossover study in healthy volunteers, omeprazole at a dose of 40 mg increased the Cmax and AUC of cilostazol by 18% and 26%, respectively, and those of one of its active metabolites by 29% and 69%, respectively. Warfarin: A clinical study showed that co-administration of TEZOL 40 mg with patients taking warfarin resulted in coagulation times within acceptable limits. However, several cases of clinically significant increases in INR have been reported in post-marketing surveillance. Monitoring is recommended when initiating and completing treatment with TEZOL in patients treated with warfarin or other coumarin derivatives. Cisapride: In healthy volunteers, co-administration of TEZOL 40 mg resulted in a 32% increase in the area under the plasma concentration/time curve (AUC) and a 31% prolongation of the elimination half-life (T 1/2 ), but peak plasma concentrations were not significantly changed. Following cisapride administration, a slight prolongation of the QTc interval was observed, but no further prolongation occurred with concomitant use with TEZOL. Clopidogrel: Studies in healthy subjects have shown a pharmacokinetic (PK)/pharmacodynamic (PD) interaction between clopidogrel (300 mg loading dose / 75 mg daily maintenance dose) and TEZOL (40 mg daily), leading to a mean reduction in exposure to the active metabolite of clopidogrel by 40% and a mean reduction in the maximum inhibition of platelet aggregation (ADP-induced) by 14%. In a study in healthy subjects, when clopidogrel was administered with a fixed combination dose of TEZOL 20 mg + ASA 81 mg, the exposure to the active metabolite of clopidogrel was reduced by almost 40% compared to administration of clopidogrel alone. However, the maximum level of ADP-induced platelet aggregation in these subjects was similar in the clopidogrel group and the clopidogrel + combination (TEZOL+ASA) product group. Both observational and clinical studies have yielded conflicting data on the clinical outcomes of TEZOL PK/PD interactions regarding cardiovascular events. Due to caution, concomitant administration of clopidogrel is not recommended. Investigated drugs without clinically significant interactions. Amoxicillin and quinidine: Esomeprazole has been shown to have no clinically significant effect on the pharmacokinetics of amoxicillin or quinidine. Naproxen or rofecoxib: Studies evaluating the co-administration of TEZOL with naproxen or rofecoxib did not reveal any clinically significant pharmacokinetic interactions during short-term studies. Medicinal products that inhibit CYP2C19 and/or CYP3A4: TEZOL is metabolized by CYP2C19 and CYP3A4. Co-administration of TEZOL with CYP3A4 inhibitor, clarithromycin (500 mg once daily), resulted in a twofold increase in TEZOL exposure (AUC). Concomitant administration of TEZOL with a combined inhibitor of CYP2C19 and CYP3A4 may lead to a twofold increase in TEZOL exposure. Voriconazole, a CYP2C19 and CYP3A4 inhibitor, increased the AUCτ of omeprazole by 280%. Dose adjustment of TEZOL is not routinely required in any of these cases. However, dose adjustment should be considered in patients with severe hepatic impairment and for long-term indications. Medicinal products that induce CYP2C19 and/or CYP3A4: Drugs known to induce CYP2C19 or CYP3A4, or both (e.g., rifampicin and St. John's wort), may lead to reduced serum levels of TEZOL due to increased metabolism of TEZOL. Pediatric Population. Interaction studies have only been conducted in adults. Overdose: To date, experience with intentional overdose is very limited. Symptoms associated with 280 mg included gastrointestinal symptoms and weakness. A single dose of 80 mg TEZOL did not cause complications. No specific antidote is known. TEZOL is highly protein-bound and therefore not readily dialyzable. As with any overdose, treatment is symptomatic along with general supportive measures. Pregnancy and lactation: Pregnancy. Clinical data on pregnancy with TEZOL exposure are insufficient. Epidemiological study data from observations of a large number of pregnancies using the racemic mixture of omeprazole did not reveal fetotoxicity or developmental defects. Animal studies have not revealed direct or indirect harmful effects of TEZOL on embryonic/fetal development. Animal studies with the racemic mixture have not revealed direct or indirect harmful effects on pregnancy, childbirth, or the postnatal development period. Caution is advised when prescribing to pregnant women. A moderate number of data in pregnant women (300-1000 pregnancy outcomes) do not indicate malformative or feto/neonatal toxicity of TEZOL. Animal studies have not shown direct or indirect harmful effects regarding reproductive toxicity. Lactation. It is unknown whether TEZOL is excreted in human breast milk. Information on the effect of TEZOL on newborns/infants is insufficient. TEZOL should not be used during lactation. Fertility. Animal studies with oral administration of the racemic mixture of omeprazole did not indicate an effect on fertility. Special precautions: In the presence of any alarming symptoms (e.g., significant unintentional weight loss, recurrent vomiting, dysphagia, hematemesis or melena) and in case of suspected or existing gastric ulcer, malignancy should be excluded, as treatment with TEZOL may mask symptoms and delay diagnosis. Long-term use. Patients on long-term treatment (especially for more than one year) should be under regular supervision. Helicobacter pylori eradication. When prescribing TEZOL for Helicobacter pylori eradication, potential drug interactions of all components of triple therapy should be considered. Clarithromycin is a potent inhibitor of CYP3A4 and therefore contraindications and interactions of clarithromycin should be considered when triple therapy is used in patients concomitantly taking drugs metabolized by CYP3A4, such as cisapride. Gastrointestinal infections. Treatment with proton pump inhibitors may lead to a slightly increased risk of gastrointestinal infections, such as Salmonella and Campylobacter. Vitamin B12 absorption. TEZOL, like other acid-blocking drugs, may reduce vitamin B12 (cyanocobalamin) absorption due to hypo- or achlorhydria. This should be considered for long-term therapy in patients with reduced vitamin B12 stores or risk factors for impaired absorption of vitamin B12. Hypomagnesemia. Severe hypomagnesemia has been reported in patients treated with proton pump inhibitors (PPIs), such as TEZOL, for at least three months and in most cases for one year. Serious manifestations of hypomagnesemia, such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia, may be asymptomatic and go unnoticed. In most cases, hypomagnesemia improved after replacement therapy with magnesium preparations and discontinuation of PPIs. In patients on long-term treatment or who take PPIs with digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), magnesium levels should be measured before initiating PPI treatment and periodically during treatment. Fracture risk. Proton pump inhibitors, especially at high doses and for long-term use (more than 1 year), may slightly increase the risk of hip, wrist, and spine fractures, mainly in elderly patients or in the presence of other known risk factors. According to observational studies, proton pump inhibitors may increase the overall risk of fractures by 10-40%. This increase may be related to other risk factors. Patients at risk of osteoporosis should receive treatment according to current clinical guidelines and should receive adequate vitamin D and calcium. Subcutaneous lupus erythematosus (SCLE). Proton pump inhibitors have been associated with very rare cases of SCLE. If lesions occur, especially in sun-exposed areas of the skin, and if accompanied by arthralgia, TEZOL administration should be discontinued. Previous treatment with proton pump inhibitors may increase the risk of SCLE to other proton pump inhibitors. Combination with other medicinal products. Concomitant administration of TEZOL with atazanavir is not recommended. If combination of atazanavir with a proton pump inhibitor is unavoidable, careful clinical monitoring is recommended with an increase in atazanavir dose to 400 mg with 100 mg ritonavir; the dose of TEZOL should not exceed 20 mg. TEZOL is a CYP2C19 inhibitor. When initiating or discontinuing TEZOL treatment, potential interactions with drugs metabolized by CYP2C19 should be considered. An interaction between clopidogrel and TEZOL has been established. The clinical significance of this interaction is unknown. Due to caution, concomitant administration of TEZOL and clopidogrel should be discontinued. When initiating TEZOL therapy on an as-needed basis, the consequences of interactions with other pharmaceutical agents due to fluctuations in TEZOL plasma concentration should be considered. Severe skin reactions (SCARs). Severe skin reactions (SCARs), such as erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening, have been reported very rarely in association with TEZOL treatment. Effect on laboratory tests. Increased levels of chromogranin A (CgA) may interfere with neuroendocrine tumor investigations. To avoid this effect, TEZOL treatment should be discontinued at least five days before CgA determination and repeated 14 days after discontinuation of PPI treatment. Sodium. This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is essentially "sodium-free". Effect of the preparation on the ability to drive and use machinery: TEZOL has a minor influence on the ability to drive or use machinery. Adverse reactions such as dizziness (uncommon) and blurred vision (rare) have been reported. If these symptoms occur, patients should not drive or operate machinery. Packaging: 10 tablets in a blister, 2 blisters in a cardboard box. Storage conditions: Store at a temperature not exceeding 25°C in the original packaging. Keep out of reach of children. Administration of the preparation is not allowed in case of any visible defects. Shelf life: 2 years. The preparation must not be used after the expiry date indicated on the packaging. Conditions of dispensing from the pharmacy: Pharmaceutical product group III, available without a prescription.