Instructions for Nolpaza gastro-resistant tablets 40 mg No. 28
Composition
active ingredient: pantoprazole;
1 gastro-resistant tablet contains 40 mg of pantoprazole in the form of pantoprazole sodium sesquihydrate;
Excipients: mannitol (E 421), crospovidone (type A), crospovidone (type B), anhydrous sodium carbonate, sorbitol (E 420), calcium stearate, hypromellose, povidone, titanium dioxide (E 171), yellow iron oxide (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
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 hydrochloric acid in the stomach. 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, as with other proton pump inhibitors (PPIs) and H2-receptor inhibitors, reduces acidity in the stomach 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, they do not exceed the upper limit of normal in most cases. In long-term treatment, gastrin levels increase by a factor of two in most cases. Excessive increases occur only in isolated cases. As a result, in a small number of cases, a mild to moderate increase in specific endocrine (ECL) cells in the stomach (similar to adenomatoid hyperplasia) has been observed during long-term treatment. However, according to the studies conducted so far, the formation of precursor cells for 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, an effect of long-term (more than one year) treatment with 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
Absorption. Pantoprazole is rapidly absorbed and peak plasma concentrations are reached after a single oral dose of 40 mg. On average, peak serum concentrations of approximately 2-3 μg/ml are reached 2.5 hours after administration; concentrations remain constant after multiple dosing. The pharmacokinetic properties do not change after single or repeated dosing. In the dose range of 10 to 80 mg, the pharmacokinetics of pantoprazole in plasma 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 concentration, 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 not much longer than that of pantoprazole.
Special patient groups.
Poor metabolisers. Approximately 3% of Europeans have a functional deficiency 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 dosage of pantoprazole.
Renal impairment. There are no recommendations for dose reduction when prescribing pantoprazole to patients with reduced 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 7-9 hours and the AUC increases 5-7-fold, the maximum serum concentration increases only slightly - 1.5-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.
- 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.
- Stomach ulcer.
- Zollinger-Ellison syndrome and other hypersecretory pathological conditions.
Contraindication
Hypersensitivity to the active substance, benzimidazole derivatives or to any component 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
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.
Interactions of pantoprazole with other drugs that are metabolized through the same enzyme system cannot be excluded.
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
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.
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 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).
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. With long-term treatment, especially more than 1 year, patients should be under regular medical supervision.
Gastrointestinal infections caused by bacteria
Treatment with the drug 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 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
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, should be taken 1 hour before meals whole, do not chew or crush, and drink water.
Recommended dosage.
Adults and children aged 12 and over.
Treatment of reflux esophagitis.
The recommended dose is 1 tablet of Nolpaza 40 mg per day. In some cases, the dose can be doubled (2 tablets of Nolpaza 40 mg per day), especially if other drugs for the treatment of reflux esophagitis have not had an effect. Reflux esophagitis usually takes 4 weeks to treat. If this is not enough, healing can be expected within another 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 Nolpaza 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 Nolpaza 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 Nolpaza 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 the eradication of H. pylori, the second tablet of Nolpaza 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 of no more than two weeks. If further treatment with pantoprazole is indicated to ensure ulcer healing, 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, Nolpaza 40 mg should be used for monotherapy at the dosage indicated below.
Treatment of stomach ulcers.
1 tablet of Nolpaza 40 mg per day. In some cases, the dose can be doubled
(2 tablets of Nolpaza 40 mg per day), especially if there is no effect from the use of other drugs.
Treatment of duodenal ulcers.
1 tablet of Nolpaza 40 mg per day. In some cases, the dose can be doubled
(2 tablets of Nolpaza 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 Nolpaza 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.
Patients with hepatic impairment. Patients with severe hepatic impairment should not exceed a daily dose of 20 mg (1 tablet of Nolpaza 20 mg). Nolpaza 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. Nolpaza should not be used for the eradication of H. pylori in combination therapy 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
Nolpaza 40 mg is indicated in children aged 12 years and older for the treatment of reflux esophagitis. The drug is not recommended for use in children under 12 years of age, as data on safety and efficacy in this age group are limited.
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%).
Adverse effects are classified by 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 based on available data).
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"), 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 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: 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.
