Instructions for use Topraz gastro-resistant tablets 20 mg blister No. 30
Composition
active ingredient: pantoprazole;
1 gastro-resistant tablet contains pantoprazole sodium sesquihydrate equivalent to pantoprazole 20 mg;
Excipients: mannitol (E 421), crospovidone, sodium carbonate anhydrous, hydroxypropylcellulose, calcium stearate, hypromellose, iron oxide yellow (E 172), methacrylate copolymer dispersion, triethyl citrate.
Dosage form
Gastro-resistant tablets.
Main physicochemical properties: 20 mg tablets: light yellow, enteric-coated, oval biconvex tablets, smooth on both sides.
Pharmacotherapeutic group
A drug for the treatment of acid-dependent diseases. Proton pump inhibitors. ATC code A02B C02.
Pharmacological properties
Pharmacodynamics.
Mechanism of action. Pantoprazole is a substituted benzimidazole that inhibits gastric acid secretion by specific blockade of the proton pumps of 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. Inhibition is dose-dependent and affects 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 cell 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, it does not exceed the upper limit of normal in most cases. In long-term treatment, gastrin levels are doubled in most cases. Excessive increases occur only in isolated cases. As a result, a small number of patients with long-term treatment have a mild to moderate increase in specific endocrine (ECL) cells in the stomach (similar to adenomatoid hyperplasia). However, according to studies, the formation of precursor cells of neuroendocrine tumors (atypical hyperplasia) or neuroendocrine tumors of the stomach, which have been observed in animal studies, has not been observed in humans.
Based on the results of animal studies, the effect of long-term (more than one 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 PPI 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 the maximum plasma concentration (Cmax) is reached after a single oral dose of 20 mg. On average, Cmax of about 1–1.5 μg/ml is reached 2–2.5 hours after administration; the concentration does not change after multiple administration of the drug. The pharmacokinetic properties do not change after single or repeated administration. In the dose range from 10 to 80 mg, the pharmacokinetics of pantoprazole in blood plasma remains linear both after oral and intravenous administration. It has been established that the absolute bioavailability of tablets is about 77%. Simultaneous food intake does not affect AUC (area under the concentration-time curve) or Cmax, and, accordingly, bioavailability. With simultaneous food intake, only the variability of the latent period increases.
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. Elimination. The terminal half-life (T1/2) is about 1 hour and the clearance is 0.1 l/h/kg. Several cases of delayed elimination have been reported. Due to the specific binding of pantoprazole to the proton pumps of the parietal cells, the T1/2 does not correspond to the much longer duration of action (inhibition of acid secretion).
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. T1/2 of the main metabolite (about 1.5 hours) is not much longer than T1/2 of pantoprazole.
Slow metabolizers.
About 3% of Europeans have a low functional activity of the CYP2C19 enzyme; these people 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 AUC was approximately 6 times higher in poor metabolisers than in subjects with a functionally active CYP2C19 enzyme (extensive metabolisers). The mean Cmax was increased by approximately 60%. These findings do not affect the dosage of pantoprazole.
Patients with renal failure.
There are no recommendations for reducing the dose of pantoprazole in patients with reduced renal function, including patients on dialysis. As in healthy subjects, the T1/2 of pantoprazole is short. Only very small amounts of pantoprazole are dialyzed. Although the main metabolite has a moderately long T1/2 (2–3 hours), elimination is rapid, so accumulation does not occur.
Patients with liver failure.
Although in patients with cirrhosis (Child-Pugh classes A and B) T1/2 increases to 3–6 hours and AUC increases 3–5-fold, Cmax increases only slightly – 1.3-fold compared to that in healthy volunteers.
Elderly patients.
The small 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 age or body weight. The AUC and volume of distribution were consistent with those obtained in adult studies.
Indication
Adults and children aged 12 and over.
- Symptomatic treatment of gastroesophageal reflux disease.
- Long-term treatment and prevention of relapses of reflux esophagitis.
Adults.
- Prevention of gastric and duodenal ulcers caused by taking non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk who must use NSAIDs for a long time.
Contraindication
Hypersensitivity to the active substance, benzimidazole derivatives or to any other component of the medicinal product.
Interaction with other medicinal products and other types of interactions
Drugs whose absorption depends on pH.
Due to the complete and long-term inhibition of hydrochloric acid secretion, pantoprazole may reduce the absorption of drugs whose bioavailability depends on the pH of the gastric juice (e.g. some antifungal drugs such as ketoconazole, itraconazole, posaconazole, or other drugs such as erlotinib).
HIV protease inhibitors.
The concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir), the absorption of which 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 PPIs 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 fatal outcome. In such concomitant use, INR and prothrombin time should be monitored.
Methotrexate.
Concomitant use of high doses of methotrexate (e.g. 300 mg) and PPIs has been reported to increase blood levels of methotrexate in some patients. Patients receiving high doses of methotrexate, e.g. for cancer or psoriasis, are advised to temporarily discontinue pantoprazole treatment.
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.
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 ensures the absorption of digoxin.
No interactions with concomitantly administered antacids were identified.
Studies have been conducted on the interaction of pantoprazole with certain antibiotics (clarithromycin, metronidazole, amoxicillin) administered concomitantly. No clinically significant interactions between these drugs have been identified.
Drugs 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 affecting CYP2C19 and CYP3A4, such as rifampicin and St. John's wort (Hypericum perforatum), may reduce plasma concentrations of PPIs 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 with the drug should be discontinued.
Concomitant use with NSAIDs.
The use of the drug Topraz, gastro-resistant tablets 20 mg, for the prevention of gastric and duodenal ulcers caused by long-term use of NSAIDs should be limited to patients who are prone to frequent exacerbations of gastric and duodenal ulcers.
Risk assessment is based on individual risk factors, including age (> 65 years), history of gastric or duodenal ulcer, and gastrointestinal bleeding.
Gastric malignancies. Symptomatic response to pantoprazole may mask the 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), as well as in the presence or suspicion of gastric ulcer, malignancy should be excluded.
If symptoms persist despite adequate treatment, further examination is necessary.
HIV protease inhibitors: 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).
Vitamin B12 absorption: Pantoprazole 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 risk factors for reduced absorption of vitamin B12 during long-term treatment, or in the presence of relevant clinical symptoms.
Long-term treatment. With long-term treatment, especially more than one year, patients should be under regular medical supervision.
Gastrointestinal infections caused by bacteria. Treatment with this medicine may slightly increase the risk of developing gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or Clostridium 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 one 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.
Patients requiring long-term therapy or patients taking PPIs concomitantly with digoxin or drugs that may cause hypomagnesemia (e.g., diuretics) should have their magnesium levels measured before starting PPI treatment and periodically during treatment.
Subacute cutaneous lupus erythematosus. The use of PPIs 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 the drug. The occurrence of subacute cutaneous lupus erythematosus in patients on previous PPI therapy may increase the risk of its development with other PPIs.
Impact on laboratory test results.
Elevated chromogranin A (CgA) levels may interfere with the diagnostic tests for neuroendocrine tumors. To avoid this interference, treatment with the drug should be temporarily discontinued for at least 5 days before CgA measurements (see section 5.2). 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 PPI treatment.
Excipients.
The tablets contain mannitol, which may have a mild laxative effect.
Use during pregnancy or breastfeeding
Pregnancy: Available data on the use of pantoprazole in pregnant women (approximately 300-1000 pregnancy outcomes) indicate no embryonal or foeto-neonatal toxicity of the drug. Reproductive toxicity has been observed in animal studies. As a precautionary measure, the use of the drug in pregnant women should be avoided.
Breast-feeding. Animal studies have shown excretion of pantoprazole in breast milk. There is insufficient information on the excretion of pantoprazole in human milk, but such excretion has been reported. A risk to the newborn/infants cannot be excluded. A decision to discontinue breast-feeding or to discontinue/abstain from the drug should be made taking into account the benefit of therapy for the mother/risk to the child.
Fertility: Pantoprazole did not impair fertility in animal studies.
Ability to influence reaction speed when driving vehicles or other mechanisms
Pantoprazole has no or very little effect on the ability to drive or use machines. It is necessary to take into account the possible development of side effects such as dizziness and visual disturbances. In such cases, you should not drive or use machines.
Method of administration and doses
Topraz, gastro-resistant tablets, should be taken 1 hour before meals whole, not chewed or crushed, with water.
Recommended dosage.
Adults and children aged 12 and over.
Symptomatic treatment of gastroesophageal reflux disease.
The recommended dose is 20 mg (1 tablet) of Topraz per day. Usually, heartburn symptoms disappear within 2-4 weeks. If this period is not enough, treatment should be continued for another 4 weeks. After the symptoms disappear, the recurrence of symptoms can be controlled by using 20 mg of the drug 1 time per day, taking 1 tablet when necessary. The transition to long-term therapy should be considered in cases where satisfactory control of symptoms is not provided by on-demand therapy.
Long-term treatment and prevention of reflux esophagitis recurrence.
For long-term treatment, the maintenance dose is 20 mg (1 tablet) of Topraz per day, with exacerbation of the disease, the dose may be increased to 40 mg per day. In this case, it is recommended to take Topraz 40 mg tablets. After the relapse is eliminated, the dose can be reduced again to 20 mg of the drug per day.
Adults.
Prevention of gastric and duodenal ulcers caused by taking non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk who must take NSAIDs for a long time.
The recommended dose is 20 mg (1 tablet) of Topraz per day.
Hepatic impairment: Patients with severe hepatic impairment should not exceed a dose of 20 mg (1 tablet) per day.
Renal impairment: Patients with renal impairment do not require dose adjustment.
Elderly patients do not require dose adjustment.
Children: The drug is not recommended for use in children under 12 years of age, as data on the safety and efficacy of the drug in 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 approximately 1% of patients).
For all adverse reactions reported during the post-marketing period, it is not possible to determine the frequency, therefore they are listed as "frequency unknown".
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).
From the side of metabolism and metabolism.
Rare: hyperlipidemia and increased lipid levels (triglycerides, cholesterol), weight change.
Not known: hyponatremia, hypomagnesemia (see section "Special warnings and precautions for use"), hypocalcemia1, hypokalemia.
Mental disorders.
Uncommon: sleep disorders.
Rare: depression (including exacerbation).
Very rare: disorientation (including exacerbation).
Not known: hallucination, confusion (especially in patients with a predisposition to such 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 digestive tract.
Common: fundal gland polyps (benign).
Uncommon: diarrhoea, nausea, vomiting, abdominal bloating, constipation, dry mouth, abdominal pain and discomfort.
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").
On the part of the musculoskeletal system and connective tissue.
Uncommon: fractures of the hip, wrist, spine (see section "Special warnings and precautions for use").
Rare: arthralgia, myalgia.
Not known: muscle spasm2.
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.
1 Hypocalcemia concomitant with hypomagnesemia.
2 Muscle spasm as a result of electrolyte imbalance.
Reporting of suspected adverse reactions.
It is important to report suspected adverse reactions after the marketing authorisation of a medicinal product. This will allow for continued monitoring of the benefit/risk balance. Healthcare professionals are requested to report suspected adverse reactions via the national reporting system.
Expiration date
2 years.
Storage conditions
Store out of the reach of children at a temperature not exceeding 25 °C.
Packaging
10 tablets in a blister; 3 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Aurobindo Pharma Limited - Unit VII.
Location of the manufacturer and address of the place of business.
Special Economic Zone, TSIIC, Plot No. S1, Sy. Nos. 411/P, 425/P, 434/P, 435/P and 458/P Green Industrial Park, Polepally Village, Jedcherla Mandal, Mahaboobnagar District, Telangana State, 509302, India.
