Instructions for Nolpaza gastro-resistant tablets 20 mg No. 28
Composition
active ingredient: pantoprazole;
1 gastro-resistant tablet contains 20 mg of pantoprazole as pantoprazole sodium sesquihydrate;
Excipients: mannitol (E 421), crospovidone (type A), crospovidone (type B), sodium carbonate anhydrous, sorbitol (E 420), calcium stearate, hypromellose, povidone, titanium dioxide (E 171), iron oxide yellow (E 172), propylene glycol, methacrylate copolymer dispersion, sodium lauryl sulfate, polysorbate 80, talc, macrogol 6000.
Dosage form
Gastro-resistant tablets.
Main physicochemical properties: light yellow-brown tablets, oval, slightly biconvex, film-coated.
Pharmacotherapeutic group
Proton pump inhibitors. ATX code A02B C02.
Pharmacological properties
Pharmacodynamics
Pantoprazole is a substituted benzimidazole that blocks the secretion of hydrochloric acid in the stomach through a specific effect on the proton pump of parietal cells.
Pantoprazole is transformed into the active form in an acidic environment, namely in the parietal cells, where it inhibits the enzyme H+-K+-ATPase, i.e. blocks the final stage of hydrochloric acid production in the stomach. Inhibition is dose-dependent and suppresses both basal and stimulated acid secretion.
Treatment with pantoprazole, like other proton pump inhibitors (PPIs) and H2-receptor inhibitors, reduces gastric acidity and thus increases gastrin secretion in proportion to the reduction 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 independently of stimulation by other substances (acetylcholine, histamine, gastrin). The efficacy of the drug is the same when administered orally or intravenously.
When using pantoprazole, fasting gastrin levels increase. In short-term use, they do not exceed the upper limit of normal in most cases. In long-term treatment, gastrin levels in most cases increase by half. Their excessive increase occurs only in isolated cases. As a result, in a small number of cases, during long-term treatment, a slight or moderate increase in the number of enterochromaffin-like cells (ECL cells) of the stomach (adenomatoid hyperplasia) is observed. However, according to the studies conducted so far, the formation of precursor cells of neuroendocrine tumors of the stomach, which was detected in animal experiments, has not been observed in humans. However, with long-term (more than 1 year) treatment, the effect of pantoprazole on endocrine parameters of the thyroid gland cannot be 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
Pantoprazole is rapidly absorbed, with peak plasma concentrations occurring even after a single dose of 40 mg. On average, peak plasma concentrations of 2-3 μg/ml are reached within 2.5 hours after administration and remain constant even after multiple administration. The volume of distribution is approximately 0.15 l/kg and the clearance is approximately 0.1 l/h/kg.
The elimination half-life is approximately 1 hour. In a few cases the elimination time was prolonged. Due to the specific binding of pantoprazole to the proton pump of the parietal cells, the elimination half-life does not correlate with a longer duration of action.
The pharmacokinetics are not affected by single or multiple dosing. At doses from 10 to 80 mg, the kinetics of pantoprazole in blood plasma are linear after both oral and intravenous administration.
The plasma protein binding of pantoprazole is approximately 98%. The drug is almost completely metabolized in the liver. The main route of excretion is the kidneys - approximately 80% of the metabolites of pantoprazole; the rest is excreted in the feces. The main metabolite in both plasma and urine is desmethylpantoprazole, which is bound to sulfate. The half-life of the main metabolite (approximately 1.5 hours) is slightly longer than that of pantoprazole.
Bioavailability. After oral administration, pantoprazole is completely absorbed. The absolute bioavailability of the tablet is approximately 77%. Food intake has no effect on the area under the pharmacokinetic concentration-time curve (AUC), maximum plasma concentration and bioavailability; only the onset of action is altered.
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.
For patients with impaired renal function (including patients on hemodialysis), no dose reduction is required. As in healthy subjects, the elimination half-life of pantoprazole is short. Only very small amounts of pantoprazole are dialyzed. Although the elimination half-life of the main metabolite is slightly increased (2-3 hours), it is rapidly excreted and therefore does not accumulate.
In patients with liver cirrhosis (Child-Pugh classes A and B), the half-life increases to 7-9 hours and, accordingly, the AUC value increases 5-7 times and the maximum concentration of pantoprazole in the blood plasma increases by 1.5 times compared to healthy people.
The slight increase in AUC and maximum plasma concentration of pantoprazole in elderly volunteers compared to young volunteers is also not clinically significant.
Elderly patients: The 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
There was no significant relationship between pantoprazole clearance and age or body weight in subjects aged 16 years and older. AUC and volume of distribution were consistent with those observed in adults.
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 need to use NSAIDs for a long time.
Contraindication
Hypersensitivity to pantoprazole, benzimidazole derivatives or any other substance included in the composition of the drug.
Interaction with other medicinal products and other types of interactions
Medicinal products whose absorption is pH-dependent: 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 antifungals such as ketoconazole, itraconazole, posaconazole, or other medicinal products such as erlotinib).
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 4.4).
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 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 proton pump inhibitors 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.
Research on other interactions
Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19 and other metabolic pathways, including oxidation by CYP3A4.
Studies with drugs that are also metabolized by these pathways, such as carbamazepine, diazepam, glibenclamide, nifedipine, phenprocoumon and oral contraceptives containing levonorgestrel and ethinyl estradiol, have not revealed clinically significant interactions.
The results of interaction studies indicate that pantoprazole does not affect the metabolism of active substances metabolised by CYP1A2 (such as caffeine and theophylline), CYP2C9 (e.g. piroxicam, diclofenac, naproxen), CYP2D6 (e.g. metoprolol), CYP2E1 (e.g. ethanol) or does not affect p-glycoprotein, which ensures the absorption of digoxin.
No interactions with concomitantly administered antacids were identified.
Special studies have been conducted on the interaction of pantoprazole with certain antibiotics (clarithromycin, metronidazole, amoxicillin) when used simultaneously. 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
Patients with hepatic impairment
In case of severe liver dysfunction during treatment with the drug, especially during long-term use, regular monitoring of liver enzyme levels is necessary. In case of increased liver enzyme levels, treatment should be discontinued.
Concomitant use with NSAIDs.
The use of Nolpaza, gastro-resistant tablets 20 mg, for the prevention of gastric and duodenal ulcers caused by long-term use of NSAIDs should be limited in 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.
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).
Effect on vitamin B12 adsorption
Pantoprazole may reduce the absorption of vitamin B12 (cyanocobalamin) due to the occurrence of hypo- or achlorhydria. This should be taken into account in patients with low body weight or risk factors for reduced absorption of vitamin B12 (cyanocobalamin), especially during long-term treatment or in the presence of relevant clinical symptoms.
Long-term treatment
If the duration of treatment exceeds 1 year, the patient should be under constant supervision.
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.
Hypomagnesemia: Severe hypomagnesemia has been reported in patients treated with PPIs such as pantoprazole for at least three 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.
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.
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 those with other risk factors. Observational studies suggest that proton pump inhibitor use may increase the overall risk of fractures in
10-40%. Some of these may be due to other risk factors. Patients at risk of osteoporosis should receive treatment according to current clinical guidelines and consume sufficient vitamin D and calcium.
Gastrointestinal infections caused by bacteria
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 this is accompanied by arthralgia, the patient should immediately consult a doctor who will consider the need to discontinue the use of Nolpaza. The occurrence of subacute cutaneous lupus erythematosus in patients during previous therapy with proton pump inhibitors may increase the risk of its development with the use of other proton pump inhibitors.
Impact on laboratory test results.
Elevated levels of chromogranin A (CgA) may interfere with the results of tests for the diagnosis of neuroendocrine tumors. To avoid this interference, treatment with Nolpaza 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 the initial measurement, repeat measurements should be performed 14 days after discontinuation of proton pump inhibitor treatment.
Information on excipients
Nolpaza contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not use this medicine.
Use during pregnancy or breastfeeding
Pregnancy. Available data on the use of Nolpaza in pregnant women indicate no embryonal or foeto/neonatal toxicity of the drug. Reproductive toxicity has been observed in animals. As a precautionary measure, the use of Nolpaza in pregnant women should be avoided.
Breastfeeding. 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 on whether to discontinue breast-feeding or to discontinue/abstain from Nolpaza therapy should be made taking into account the benefit of breast-feeding for the child and the benefit of Nolpaza therapy for the woman.
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 minor influence 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 (see section "Adverse reactions"). In such cases, you should not drive or use machines.
Method of administration and doses
Nolpaza, gastro-resistant tablets of 20 mg, should be taken 1 hour before meals whole, do not chew or crush, and washed down 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 Nolpaza per day. Usually, heartburn symptoms disappear within 2-4 weeks. If this period is not enough, treatment is continued for another 4 weeks. After the symptoms disappear, their recurrence can be controlled by using 20 mg of the drug depending on the need.
Long-term treatment and prevention of reflux esophagitis recurrence.
For long-term treatment, the maintenance dose is 20 mg (1 tablet) of Nolpaza 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 Nolpaza 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 Nolpaza 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 should not be used in children under 12 years of age.
Overdose
Symptoms of overdose are unknown.
Doses up to 240 mg given intravenously over 2 minutes have been well tolerated. Since pantoprazole is extensively bound to blood proteins, it is not readily dialyzable.
In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy should be used. There are no specific treatment recommendations.
Adverse reactions
Adverse reactions were observed in approximately 5% of patients. The most common adverse reactions were diarrhea and headache (approximately 1%).
Undesirable effects are classified according to the frequency of occurrence into the following categories: very common
(≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10000 and < 1/1000), very rare (< 1/10000), unknown (frequency not determined from available data).
From the blood and lymphatic system.
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"), 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 these disorders, as well as exacerbation of these symptoms in case of their pre-existence).
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: fundic 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.
Expiration date
5 years.
Storage conditions
Store at a temperature not exceeding 30 ° C in the original packaging to protect from moisture. Keep out of the reach of children.
Packaging
14 tablets in a blister; 1 or 2 or 4 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
KRKA, dd, Novo mesto, Slovenia.
Address
Smarjeska cesta 6, 8501 Novo mesto, Slovenia.
