Instructions for Ulsepan enteric-coated tablets 40 mg No. 28
Composition
active ingredient: pantoprazole;
1 enteric-coated tablet contains pantoprazole (in the form of pantoprazole sodium sesquihydrate) 40 mg;
excipients:
core: mannitol (E 421), calcium carbonate, crospovidone, povidone, sucrose stearate, calcium stearate;
film coating: Opadry white YS-1-7027 (hypromellose, titanium dioxide (E 171), glycerol triacetate);
enteric coating: Acryl-Eze yellow 93092157 (methacrylate copolymer (type C), talc, titanium dioxide (E 171), triethyl citrate, colloidal anhydrous silica, sodium bicarbonate, yellow iron oxide (E 172), sodium lauryl sulfate).
Dosage form
Enteric-coated tablets.
Main physicochemical properties: oval biconvex yellow tablets, coated.
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 parietal cell proton pumps.
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 stage of hydrochloric acid production in the stomach. Inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. In most patients, symptoms disappear within 2 weeks. The use of pantoprazole, like other proton pump inhibitors (PPIs) and H2-histamine 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 of oral and intravenous administration of pantoprazole is the same.
Pantoprazole increases fasting gastrin levels. In short-term use, gastrin levels are usually not above the upper limit of normal, and in long-term use, they are often doubled. However, excessive increases occur only in rare cases. As a result, a small number of patients with long-term use of pantoprazole have a mild to moderate increase in the number of enterochromaffin-like cells (ECL cells) in the stomach (similar to adenomatoid hyperplasia). However, according to studies, the formation of precursor cells for neuroendocrine tumors (atypical hyperplasia) or neuroendocrine tumors of the stomach, which have been observed in animal experiments, has not been observed in humans.
Based on the results of animal studies, the effect of long-term (more than one year) use of pantoprazole on endocrine parameters of the thyroid gland cannot be excluded.
During treatment with antisecretory agents, plasma 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 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 40 mg. On average, Cmax is reached 2.5 hours after administration at a level of about 2–3 μg/ml; the concentration remains the same after multiple administration. The pharmacokinetic properties do not change after a single or repeated administration. When using pantoprazole at a dose of 10–80 mg, the pharmacokinetics of pantoprazole in blood plasma remain linear both when taken orally and when administered intravenously. It has been established that the absolute bioavailability of tablets is about 77%. Simultaneous food intake does not affect the area under the concentration-time curve (AUC) or Cmax, respectively - and bioavailability. When taken simultaneously with food, only the variability of the latent period increases.
Distribution.
The binding of pantoprazole to plasma proteins is about 98%. The volume of distribution is about 0.15 l/kg.
Metabolism.
Pantoprazole 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.
Breeding.
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 plasma and urine is desmethylpantoprazole, conjugated with sulfate. T1/2 of the main metabolite (about
1.5 hours) slightly exceeds the T1/2 of pantoprazole.
Special patient groups.
Slow metabolizers.
Approximately 3% of Europeans have low functional activity of the CYP2C19 enzyme (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 functionally active CYP2C19 enzyme (extensive metabolisers). The mean Cmax increased by approximately 60%. These findings do not influence the posology of pantoprazole.
Patients with renal impairment.
No dosage adjustment is necessary in such patients (including patients on dialysis). As in healthy volunteers, the T1/2 of pantoprazole is short. Only a very small amount of pantoprazole is dialyzed. Although the main metabolite has a moderately long T1/2 (2–3 hours), its elimination is rapid, so cumulation does not occur.
Patients with liver dysfunction.
Although in patients with liver cirrhosis (Child-Pugh classes A and B) T1/2 increases to 7–9 hours and AUC increases 5–7-fold, Cmax 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 mg 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 similar to those 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.
Stomach ulcer.
Zollinger-Ellison syndrome and other hypersecretory pathological conditions.
Contraindication
Hypersensitivity to the active substance, benzimidazole derivatives and other components of the drug.
Interaction with other medicinal products and other types of interactions
Drugs whose bioavailability depends on gastric pH (e.g., some antifungals such as ketoconazole, itraconazole, posaconazole, or erlotinib)
When used simultaneously, pantoprazole may reduce the absorption of drugs whose bioavailability depends on the pH of gastric juice.
HIV protease inhibitors (atazanavir)
Concomitant use of PPIs with atazanavir and other HIV protease inhibitors whose bioavailability depends on gastric pH may significantly reduce the absorption of the latter and affect their efficacy (see section 4.4). Concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir) is not recommended. If concomitant use 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 the 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 cases, monitoring of INR and prothrombin time is necessary.
Methotrexate
Concomitant use of high doses of methotrexate (e.g. 300 mg) and PPIs has been reported to increase plasma levels of methotrexate in some patients. Patients receiving high doses of methotrexate (e.g. cancer or psoriasis) are advised to temporarily discontinue pantoprazole.
Drugs that inhibit or induce CYP2C19
CYP2C19 inhibitors such as fluvoxamine may increase the systemic exposure of pantoprazole. A reduction in the dose of pantoprazole should be considered in patients receiving high doses of pantoprazole for long periods of time 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 the plasma concentrations of PPIs metabolised by these enzyme systems.
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 clinically significant interactions. Interactions of pantoprazole with other medicinal products metabolised by 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 interaction of pantoprazole with simultaneous use with antacids has been 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 agents have been identified.
Application features
Long-term use
With long-term use of the drug, especially more than one year, patients should be under regular medical supervision.
Use in patients with impaired liver function
Patients with severe hepatic impairment should have their liver enzymes monitored regularly, especially during long-term treatment. If liver enzymes increase, the drug should be discontinued (see section 4.2).
Use as part of combination therapy
When using the drug as part of combination therapy, the instructions for medical use of the corresponding medicines should be followed.
Risk of masking malignant gastric neoplasms
Symptomatic response to pantoprazole may mask symptoms of gastric malignancy and delay 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 investigation is necessary.
Concomitant use with 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 "Interaction with other medicinal products and other types of interactions").
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 the production of hydrochloric acid, 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 the presence of risk factors for reduced absorption of vitamin B12 during long-term use of the drug, or in the presence of relevant clinical symptoms.
Risk of developing gastrointestinal infections
Pantoprazole, like other PPIs, may increase the number of bacteria normally present in the upper gastrointestinal tract. The use of pantoprazole may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or C. difficile.
Risk of developing hypomagnesemia
Cases of severe hypomagnesemia have been reported in patients taking pantoprazole for at least 3 months, in most cases for a year. The following serious clinical manifestations of hypomagnesemia may occur and initially develop unnoticed: fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia. In the case of hypomagnesemia, in most cases the patient's condition improved after magnesium replacement therapy and discontinuation of pantoprazole. In patients requiring long-term therapy or in patients taking the drug concomitantly with digoxin or drugs that may cause hypomagnesemia (e.g. diuretics), magnesium levels should be determined before and periodically during use of the drug.
Risk of bone fractures
Long-term (more than one year) use of high doses of the drug may slightly increase the risk of fractures of the hip, wrist and spine, mainly in elderly people or in the presence of other risk factors. Observational studies indicate that the use of pantoprazole 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 use adequate amounts of vitamin D and calcium.
Pantoprazole 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 during previous treatment with pantoprazole may increase the risk of its development with other PPIs.
Impact on laboratory test results
Elevated CgA levels may interfere with the results of tests for the diagnosis of neuroendocrine tumors. To avoid this interference, the drug should be temporarily discontinued for at least 5 days before CgA levels are measured (see section 5.1). 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 PPI treatment.
Excipients
The drug contains mannitol, which may have a mild laxative effect.
The drug contains sucrose, so it should not be used in patients with rare hereditary disorders of carbohydrate metabolism, in particular galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially sodium-free.
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. Reproductive toxicity has been observed in animal studies. As a precautionary measure, the use of the drug in pregnant women should be avoided.
Breastfeeding period.
Animal studies have shown excretion of pantoprazole in breast milk. There are no data 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 must be made whether to discontinue breast-feeding or to discontinue/abstain from the drug taking into account the benefit of breast-feeding for the child and the benefit of pantoprazole 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. The possible development of adverse reactions such as dizziness and visual disturbances should be taken into account (see section "Adverse reactions"). In the event of such adverse reactions, driving or using machines should be avoided.
Method of administration and doses
The drug is intended for oral use. The tablets should be taken 1 hour before meals whole, without chewing or crushing, with water.
Adults and children aged 12 and over
Reflux esophagitis
The recommended dose is 40 mg (1 tablet) once a day. In some cases, the dose can be doubled to 80 mg (2 tablets) per day, especially if other medications are ineffective. Reflux esophagitis usually requires 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 with combination therapy. Local data on bacterial resistance and national guidelines for the prescription and use of appropriate antibacterial agents should be taken into account. Depending on the susceptibility of the microorganisms, the following therapeutic combinations may be prescribed for the eradication of H. pylori in adults:
a) 40 mg (1 tablet) of pantoprazole 2 times a day
+ 1000 mg of amoxicillin 2 times a day
+ 500 mg of clarithromycin 2 times a day;
b) 40 mg (1 tablet) of pantoprazole 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) 40 mg (1 tablet) of pantoprazole 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 used in combination therapy for the eradication of H. pylori, the second pantoprazole tablet should be taken in the evening 1 hour before a meal. The treatment period is 7 days and may be extended for a further 7 days (total duration of treatment not exceeding 2 weeks). If further treatment with pantoprazole is indicated to ensure ulcer healing, the dosing 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 should be used for monotherapy at the dosage indicated below.
The recommended dose is 40 mg (1 tablet) once a day. In some cases, the dose can be doubled to 80 mg (2 tablets) per day, especially if other medications are not effective. It usually takes 4 weeks to treat a stomach ulcer. If this is not enough, healing can be expected within another 4 weeks.
Duodenal ulcer
The recommended dose is 40 mg (1 tablet) once a day. In some cases, the dose can be doubled to 80 mg (2 tablets) per day, especially if other medications are ineffective. It usually takes 2 weeks to treat a stomach ulcer. If this is not enough, healing can be expected within another 2 weeks.
Zollinger-Ellison syndrome and other hypersecretory pathological conditions
For long-term treatment of Zollinger-Ellison syndrome and other pathological hypersecretory conditions, the recommended initial daily dose is 80 mg (2 tablets) per day. If necessary, the dose can then be titrated up or down, depending on the indicators of acid secretion in the stomach. If the dose exceeds 80 mg per day, it should be divided into two doses. A temporary increase in the dose to more than 160 mg of pantoprazole is possible, but the duration of use should be limited only to the period necessary for adequate control of acid secretion.
The duration of treatment for Zollinger-Ellison syndrome and other pathological conditions is not limited and depends on clinical need.
Patients with liver dysfunction
Patients with severe hepatic impairment should not exceed a daily dose of pantoprazole 20 mg. Patients with moderate to severe hepatic impairment should not use the drug for H. pylori eradication in combination therapy, as there is currently no data on the efficacy and safety of such use in this category of patients.
Patients with renal impairment
There is no need for dosage adjustment in such patients. Patients with impaired renal function should not use the drug for eradication of H. pylori in combination therapy, as there is currently no data on the efficacy and safety of such use in this category of patients.
Elderly patients
There is no need for dosage adjustment in such patients.
Children
The drug is used 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 the safety and efficacy of pantoprazole in this age group are limited.
Overdose
Symptoms of overdose are unknown. Doses of pantoprazole up to 240 mg administered intravenously over 2 minutes have been well tolerated.
Since pantoprazole is extensively bound to plasma proteins, it is not a drug that can be easily removed by dialysis.
In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy should be provided. There are no specific treatment recommendations.
Adverse reactions
The occurrence of adverse reactions was observed in about 5% of patients. The most common adverse reactions that occurred during the use of pantoprazole were diarrhea and headache (in about 1% of patients).
Adverse reactions 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).
Within each frequency category, adverse reactions are presented in order of decreasing seriousness.
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”.
Blood and lymphatic system disorders:
rarely - agranulocytosis; very rarely - leukopenia, thrombocytopenia, pancytopenia.
On the part of the immune system:
rarely - hypersensitivity reactions (including anaphylactic reactions, anaphylactic shock).
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.
From the psyche:
uncommon – sleep disorders; rare – depression (including exacerbation); very rare – disorientation (including exacerbation); unknown – hallucinations, 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:
infrequently - headache, dizziness; rarely - taste disturbances; unknown - paresthesia.
On the part of the organs of vision:
rarely - visual disturbances/blurred vision.
From the digestive tract:
common - fundic gland polyps (benign); uncommon - diarrhea, nausea, vomiting, abdominal distension, constipation, dry mouth, abdominal pain and discomfort; unknown - microscopic colitis.
From the hepatobiliary system:
uncommon – increased levels of liver enzymes (transaminases, gammaglutamyltransferase); rare – increased levels of bilirubin; unknown – hepatocyte damage, jaundice, hepatocellular insufficiency.
infrequently - skin rashes, exanthema, itching; rarely - urticaria, angioedema; unknown - Stevens-Johnson syndrome, Lyell's syndrome, erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special warnings and precautions for use").
Musculoskeletal and connective tissue disorders:
uncommon – fractures of the hip, wrist, spine (see section "Special warnings and precautions for use"); rare – arthralgia, myalgia; unknown – muscle spasm2.
From the kidneys and urinary system:
unknown - interstitial nephritis (with possible development of renal failure).
From the reproductive system and mammary glands:
rarely - gynecomastia.
General disorders:
infrequently - asthenia, fatigue, malaise; rarely - fever, peripheral edema.
1 Hypocalcemia concomitant with hypomagnesemia.
2 Muscle spasm as a result of electrolyte imbalance.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions that occur after the marketing authorisation of a medicinal product is of utmost importance. This allows for continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 °C in a dry, dark place out of the reach of children.
Packaging
7 tablets in a blister. 2 or 4 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
WORLD MEDICINE ILAC SAN. VE TIC. AS, Turkey.
Location of the manufacturer and address of its place of business
15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey / 15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey
Applicant
WORLD MEDICINE LLC, Ukraine/WORLD MEDICINE, LLC, Ukraine.
