Instructions for use Pantoprazole-Teva gastro-resistant tablets 40 mg blister No. 28
Composition
active ingredient: pantoprazole:
1 gastro-resistant tablet contains 40 mg of pantoprazole in the form of pantoprazole sodium sesquihydrate;
excipients: sodium hydrogen phosphate, mannitol (E 421), microcrystalline cellulose, croscarmellose sodium, magnesium stearate, hypromellose, triethyl citrate, sodium starch glycolate (type A), methacrylic acid - ethyl acrylate copolymer (1:1), iron oxide yellow (E 172).
Dosage form
Gastro-resistant tablets.
Main physicochemical properties: yellow, oval, biconvex and smooth tablets, the dimensions of which are 11.6 mm x 6 mm.
Pharmacotherapeutic group
A drug for the treatment of acid-dependent diseases. Proton pump inhibitors. ATC code A02B C02.
Pharmacological properties
Pharmacodynamics
Pantoprazole is a substituted benzimidazole that inhibits gastric acid secretion by specific blockade of the proton pumps of the parietal cells. Pantoprazole is converted to its active form in the acidic environment of the parietal cells, where it inhibits the enzyme H+/K+-ATPase, i.e. blocks the final step in the production of gastric acid. The inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. Most patients are relieved of symptoms within 2 weeks. The use of pantoprazole, like other proton pump inhibitors (PPIs) and H2-receptor inhibitors, reduces gastric acidity and thus increases gastrin secretion in proportion to the decrease in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds the enzyme distal to the cellular receptor, it can inhibit hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same when the drug is administered orally and intravenously.
Pantoprazole increases fasting gastrin levels. In short-term use, gastrin levels do not exceed the upper limit of normal in most cases. In long-term treatment, gastrin levels are doubled in most cases. However, excessive increases occur only in isolated cases. As a result, a slight or moderate increase in specific endocrine (ECL) cells in the stomach (similar to adenomatoid hyperplasia) is sometimes observed during long-term treatment. However, according to studies conducted to date, the formation of neuroendocrine tumor precursor cells (atypical hyperplasia) or neuroendocrine tumors of the stomach, which have been identified in animal studies, has not been observed in humans.
Based on the results of animal studies, the effect of long-term (more than 1 year) treatment with pantoprazole on endocrine parameters of the thyroid gland cannot be completely excluded.
During treatment with antisecretory drugs, serum gastrin levels increase in response to decreased acid secretion. In addition, chromogranin A (CgA) levels increase due to decreased gastric acidity. Elevated CgA levels may interfere with diagnostic tests for neuroendocrine tumors. Available published data suggest that proton pump inhibitor treatment should be discontinued for 5 days to 2 weeks before CgA measurements. This allows CgA levels to return to the normal range, which may be falsely elevated after PPI treatment.
Pharmacokinetics
Absorption. Pantoprazole is rapidly absorbed and peak plasma concentrations are reached after a single oral dose of 40 mg. Peak serum concentrations of approximately 2–3 μg/ml are reached on average 2.5 hours after administration; concentrations remain constant after multiple dosing. The pharmacokinetic properties are not affected by single or repeated dosing. In the dose range of 10 to 80 mg, the plasma pharmacokinetics of pantoprazole remain linear after both oral and intravenous administration. The absolute bioavailability of the tablets has been shown to be approximately 77%. Concomitant food intake does not affect AUC (area under the concentration-time curve) or peak serum concentrations, and therefore bioavailability. Only the variability of the latent period increases with concomitant food intake.
Distribution: The binding of pantoprazole to serum proteins is about 98%. The volume of distribution is about 0.15 l/kg.
Biotransformation. The substance is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation by CYP2C19 followed by sulfate conjugation; other metabolic pathways include oxidation by CYP3A4.
The main part of the metabolites of pantoprazole is excreted in the urine (about 80%), the rest is excreted in the feces. The main metabolite in both serum and urine is desmethylpantoprazole, conjugated with sulfate. The half-life of the main metabolite (about 1.5 hours) is slightly longer than that of pantoprazole.
Special patient groups.
Poor metabolisers. Approximately 3% of Europeans have a low functional activity of the CYP2C19 enzyme; they are called poor metabolisers. In these individuals, the metabolism of pantoprazole is probably mainly catalysed by the CYP3A4 enzyme. After a single dose of 40 mg pantoprazole, the mean area under the plasma concentration-time curve was approximately 6 times larger in poor metabolisers than in subjects with a functional CYP2C19 enzyme (extensive metabolisers). The mean peak plasma concentration was increased by approximately 60%. These findings do not affect the posology of pantoprazole.
Renal impairment. There are no recommendations for dose reduction when prescribing pantoprazole to patients with impaired renal function (including patients on dialysis). As in healthy subjects, the elimination half-life of pantoprazole is short. Only very small amounts of pantoprazole are dialysable. Although the main metabolite has a moderately long elimination half-life (2–3 hours), elimination is still rapid, so accumulation does not occur.
Hepatic impairment: Although in patients with cirrhosis (Child-Pugh class A and B) the half-life increases to 3-6 hours and the AUC increases 3-5-fold, the maximum serum concentration increases only slightly - 1.5-fold compared to that in healthy volunteers.
Elderly patients: A slight increase in AUC and Cmax in elderly volunteers compared to younger volunteers is also not clinically relevant.
Children: After a single oral dose of 20 or 40 mg pantoprazole, AUC and Cmax in children aged 5 to 16 years were within the range of the corresponding values in adults. After a single intravenous administration of pantoprazole at doses of 0.8 or 1.6 mg/kg to children aged 2 to 16 years, there was no significant relationship between the clearance of pantoprazole and the patient's age or body weight. The AUC and volume of distribution were consistent with those obtained in studies in adults.
Indication
Adults and children aged 12 and over.
Reflux esophagitis.
Adults.
Eradication of Helicobacter pylori (H. pylori) in patients with H. pylori-associated gastric and duodenal ulcers in combination with appropriate antibiotics. Duodenal ulcer. Gastric ulcer. Zollinger-Ellison syndrome and other hypersecretory pathological conditions.
Contraindication
Hypersensitivity to pantoprazole, benzimidazole derivatives or to any component of the drug.
Interaction with other medicinal products and other types of interactions
Effect of pantoprazole on the absorption of other medicinal products. Due to the complete and long-term inhibition of hydrochloric acid secretion, pantoprazole may affect the absorption of medicinal products for which the pH of the gastric juice is an important factor in their bioavailability (e.g. some azole antifungals such as ketoconazole, itraconazole, posaconazole, or other medicinal products such as erlotinib).
Anti-HIV drugs (atazanavir). The concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir), whose absorption depends on intragastric pH, is not recommended due to a significant reduction in their bioavailability (see section "Special warnings and precautions for use").
In cases where concomitant use of HIV protease inhibitors with proton pump inhibitors cannot be avoided, close clinical monitoring (e.g. viral load) is recommended. The daily dose of pantoprazole should not exceed 20 mg. Dose adjustment of HIV protease inhibitors may be necessary.
Coumarin anticoagulants (phenprocoumon and warfarin). Concomitant use of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon or INR (international normalized ratio). However, increases in INR and prolongation of prothrombin time have been reported in patients receiving concomitant PPIs and warfarin or phenprocoumon. Increases in INR and prolongation of prothrombin time may lead to pathological bleeding and even death. In such concomitant use, INR and prothrombin time should be monitored.
Other interactions. Pantoprazole is extensively metabolised in the liver via the cytochrome P450 enzyme system. The main route of metabolism is demethylation by CYP2C19 and other metabolic pathways, including oxidation by CYP3A4. Studies with medicinal products also metabolised by these pathways, such as carbamazepine, diazepam, glibenclamide, nifedipine and oral contraceptives containing levonorgestrel and ethinylestradiol, have not revealed any clinically significant interactions.
Interactions of pantoprazole with other drugs that are metabolized through the same enzyme system cannot be excluded.
The results of a number of studies on possible interactions indicate that pantoprazole does not affect the metabolism of active substances metabolized by CYP1A2 (e.g. caffeine, theophylline), CYP2C9 (e.g. piroxicam, diclofenac, naproxen), CYP2D6 (e.g. metoprolol), CYP2E1 (e.g. ethanol), and does not affect p-glycoprotein, which is associated with the absorption of digoxin.
No interactions with concomitantly administered antacids were identified.
Studies have been conducted to study the interaction of pantoprazole with certain antibiotics (clarithromycin, metronidazole, amoxicillin) administered concomitantly. No clinically significant interactions between these drugs have been identified.
Medicinal products that inhibit or induce CYP2C19. CYP2C19 inhibitors, such as fluvoxamine, may increase the systemic exposure of pantoprazole. A dose reduction should be considered in patients receiving long-term treatment with high doses of pantoprazole and in patients with impaired liver function. Inducers of enzymes that affect CYP2C19 and CYP3A4, such as rifampicin and St. John's wort (Hypericum perforatum), may reduce plasma concentrations of PPIs that are metabolised by these enzyme systems.
Application features
Hepatic impairment: Patients with severe hepatic impairment should have their liver enzymes monitored regularly, especially during long-term treatment. If liver enzymes increase, treatment should be discontinued (see section 4.2).
Combination therapy. During combination therapy, the instructions for medical use of the respective medicinal products must be followed.
Gastric malignancies. Symptomatic response to pantoprazole may mask symptoms of gastric malignancies and delay their diagnosis. In the presence of alarming symptoms (e.g. significant weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia, melena) and in the presence or suspicion of gastric ulcer, malignancy should be excluded. If symptoms persist despite adequate treatment, further investigation is necessary.
Concomitant use with atazanavir. Concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir) whose absorption is dependent on intragastric pH is not recommended due to a significant reduction in their bioavailability (see section 4.5). If the combination of pantoprazole with atazanavir is necessary, close clinical monitoring (e.g. viral load measurement) should be performed in conjunction with an increase in the dose of atazanavir to 400 mg with 100 mg ritonavir. The dose of pantoprazole 20 mg per day should not be exceeded.
Effect on vitamin B12 absorption. In patients with Zollinger-Ellison syndrome and other hypersecretory pathological conditions requiring long-term treatment, pantoprazole, like all drugs that block hydrochloric acid production, may reduce the absorption of vitamin B12 (cyanocobalamin) due to the occurrence of hypo- and achlorhydria. This should be taken into account in patients with low body weight or in the presence of risk factors for reduced absorption of vitamin B12 during long-term treatment, or in the presence of relevant clinical symptoms.
Long-term treatment. With a long-term treatment period, especially more than 1 year, patients should be under regular medical supervision.
Gastrointestinal infections caused by bacteria. Pantoprazole, like other PPIs, may increase the number of bacteria normally present in the upper gastrointestinal tract. Treatment with pantoprazole may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or C. Difficile.
Hypomagnesemia: Severe hypomagnesemia has been reported in patients treated with PPIs such as pantoprazole for at least 3 months, and in most cases for a year. The following serious clinical manifestations of hypomagnesemia may occur and may initially be insidious: fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmias. In the case of hypomagnesemia, the majority of patients improved after magnesium replacement therapy and discontinuation of the PPI.
Bone fractures. Long-term treatment (more than 1 year) with high doses of proton pump inhibitors may modestly increase the risk of hip, wrist, and spine fractures, mainly in the elderly or in the presence of other risk factors. Observational studies suggest that the use of proton pump inhibitors may increase the overall risk of fractures by 10–40%. Some of these may be due to other risk factors. Patients at risk of osteoporosis should be treated according to current clinical guidelines and consume adequate amounts of vitamin D and calcium.
Subacute cutaneous lupus erythematosus. The use of proton pump inhibitors has been associated with very rare cases of subacute cutaneous lupus erythematosus. If lesions occur, especially in areas exposed to sunlight, and are accompanied by arthralgia, the patient should immediately consult a doctor who will consider discontinuing pantoprazole. The occurrence of subacute cutaneous lupus erythematosus in patients on previous proton pump inhibitor therapy may increase the risk of its development with other proton pump inhibitors.
Interference with laboratory tests. Elevated chromogranin A (CgA) levels may interfere with the diagnostic tests for neuroendocrine tumours. To avoid this interference, pantoprazole treatment should be temporarily discontinued for at least 5 days before CgA measurement. If CgA and gastrin levels have not returned to the normal range after initial measurement, repeat measurements should be performed 14 days after discontinuation of proton pump inhibitor treatment.
Ability to influence reaction speed when driving vehicles or other mechanisms
It is necessary to take into account the possible development of adverse reactions, such as dizziness and visual disturbances. In such cases, one should not drive or operate other mechanisms.
Use during pregnancy or breastfeeding
Pregnancy. Experience with pantoprazole in pregnant women is limited. Reproductive toxicity has been observed in animal studies. The potential risk to humans is unknown. Pantoprazole should be used during pregnancy only if clearly needed.
Breastfeeding. Animal studies have shown excretion of pantoprazole in breast milk. There are data on the excretion of pantoprazole in human milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with pantoprazole should be made taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Method of administration and doses
Pantoprazole-Teva, gastro-resistant tablets, should be taken 1 hour before meals whole, do not chew or crush, and drink plenty of water.
Recommended dosage.
Adults and children aged 12 and over.
Treatment of reflux esophagitis.
The recommended dose is 1 tablet of Pantoprazole 40 mg per day. In some cases, the dose can be doubled (2 tablets of Pantoprazole 40 mg per day), especially if other medicines for the treatment of reflux esophagitis have not had any effect. Reflux esophagitis usually takes 4 weeks to treat. If this is not enough, healing can be expected within a further 4 weeks.
Adults.
Eradication of H. pylori in combination with two antibiotics.
In adult patients with gastric and duodenal ulcers and positive for H. pylori, eradication of the organism should be achieved using combination therapy. Local data on bacterial resistance and national guidelines for the use and prescription of appropriate antibacterial agents should be taken into account. Depending on susceptibility, the following therapeutic combinations may be prescribed for the eradication of H. pylori in adults:
a) 1 tablet of Pantoprazole-Teva 40 mg 2 times a day
+ 1000 mg of amoxicillin 2 times a day
+ 500 mg of clarithromycin 2 times a day;
b) 1 tablet of Pantoprazole-Teva 40 mg 2 times a day
+ 400–500 mg metronidazole (or 500 mg tinidazole) 2 times a day
+ 250–500 mg of clarithromycin 2 times a day;
c) 1 tablet of Pantoprazole-Teva 40 mg 2 times a day
+ 1000 mg of amoxicillin 2 times a day
+ 400–500 mg of metronidazole (or 500 mg of tinidazole) 2 times a day.
When using combination therapy for eradication of H. pylori, the second tablet of Pantoprazole-Teva 40 mg should be taken in the evening 1 hour before a meal. The treatment period is 7 days and can be extended for another 7 days with a total duration of treatment not exceeding 2 weeks. If further treatment with pantoprazole is indicated to ensure healing of the ulcer, the dosage recommendations for gastric and duodenal ulcers should be considered. If combination therapy is not indicated, for example, in patients with a negative result for H. pylori, Pantoprazole-Teva 40 mg is used for monotherapy in the dosage indicated below.
Treatment of stomach ulcers.
It usually takes 4 weeks to heal a stomach ulcer. If this is not enough, healing of the ulcer can be expected within another 4 weeks.
Treatment of duodenal ulcers.
1 tablet of the drug Pantoprazole-Teva 40 mg per day. In some cases, the dose can be doubled (2 tablets of the drug Pantoprazole-Teva 40 mg per day), especially if there is no effect from the use of other drugs.
Duodenal ulcers usually take 2 weeks to heal. If this is not enough, healing of the ulcer can be expected within another 2 weeks.
Treatment of Zollinger-Ellison syndrome and other hypersecretory pathological conditions. For long-term treatment of Zollinger-Ellison syndrome and other pathological hypersecretory conditions, the initial daily dose is 80 mg (2 tablets of Pantoprazole 40 mg). If necessary, the dose can then be titrated up or down, depending on the acidity of the gastric juice. A dose exceeding 80 mg per day should be divided into two doses. A temporary increase in the dose above 160 mg of pantoprazole is possible, but the duration of use should be limited only to the period necessary for adequate acidity control.
The duration of treatment for Zollinger-Ellison syndrome and other pathological conditions is not limited and depends on clinical need.
Special patient groups
Patients with hepatic impairment. Patients with severe hepatic impairment should not exceed a daily dose of 20 mg (1 tablet of Pantoprazole 20 mg). Pantoprazole should not be used for the eradication of H. pylori in combination therapy in patients with moderate to severe hepatic impairment, as there is currently no data on the efficacy and safety of such use in this category of patients.
Patients with renal impairment. No dose adjustment is required for patients with renal impairment. Pantoprazole should not be used in combination therapy for the eradication of H. pylori in patients with renal impairment, as there is currently no data on the efficacy and safety of such use in this category of patients.
Elderly patients do not require dose adjustment.
Children
The medicine is not recommended for use in children under 12 years of age, as data on the safety and efficacy of the drug for this age group are limited.
Overdose
Symptoms of overdose are unknown.
Doses up to 240 mg administered intravenously over 2 minutes have been well tolerated. Since pantoprazole is extensively protein bound, it is not a drug that can be readily dialyzed.
In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy is used. There are no specific therapy recommendations.
Adverse reactions
Adverse reactions can be expected to occur in approximately 5% of patients. The most common adverse reactions are diarrhea and headache, occurring in 1% of patients.
Adverse reactions are classified according to frequency as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), not known (cannot be estimated from available data).
For all adverse reactions reported during the post-marketing period, it is not possible to determine the frequency and are therefore indicated as “not known”.
Within each frequency category, adverse reactions are presented in order of decreasing seriousness.
From the blood and lymphatic system.
Rare: agranulocytosis.
Very rare: leukopenia, thrombocytopenia, pancytopenia.
From the immune system.
Rare: hypersensitivity reactions (including anaphylactic reactions, anaphylactic shock).
Metabolism and metabolic disorders.
Rare: hyperlipidemia and increased lipid levels (triglycerides, cholesterol), changes in body weight.
Not known: hyponatremia, hypomagnesemia (see section "Special warnings and precautions for use"), hypocalcemia (simultaneous with hypomagnesemia), hypokalemia.
Mental disorders.
Uncommon: sleep disorders.
Rare: depression (including exacerbation).
Very rare: disorientation (including exacerbation).
Not known: hallucinations, confusion (especially in patients with a predisposition to these disorders, as well as exacerbation of these symptoms in case of pre-existing conditions).
From the nervous system.
Uncommon: headache, dizziness.
Rare: taste disorders.
Not known: paraesthesia.
From the organs of vision.
Rare: visual disturbances/blurred vision.
From the gastrointestinal tract.
Common: glandular polyps of the gastric fundus (benign).
Uncommon: diarrhea, nausea, vomiting, abdominal bloating, constipation, dry mouth, abdominal pain and discomfort.
Not known: microscopic colitis.
On the part of the hepatobiliary system.
Uncommon: increased liver enzymes (transaminases, g-GT).
Rare: increased bilirubin levels.
Not known: hepatocyte damage, jaundice, hepatocellular failure.
On the skin and subcutaneous tissue.
Uncommon: skin rash, exanthema, pruritus.
Rare: urticaria, angioedema.
Not known: Stevens-Johnson syndrome, Lyell's syndrome, erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special warnings and precautions for use").
Uncommon: fractures of the hip, wrist, spine (see section "Special warnings and precautions for use").
Rare: arthralgia, myalgia.
Not known: muscle spasm as a result of electrolyte disturbances.
On the part of the kidneys and urinary system.
Not known: interstitial nephritis (with possible development of renal failure).
From the reproductive system and mammary glands.
Rare: gynecomastia.
General disorders.
Uncommon: asthenia, fatigue, malaise.
Rare: fever, peripheral edema.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 30 °C out of the reach of children.
Packaging
7 tablets in a blister, 4 blisters in a box.
Vacation category
According to the recipe.
Producer
Teva Pharma S.L.U.
Location of the manufacturer and its business address
Poligono Industrial Malpica c/C No. 4, 50016, Zaragoza, Spain.
