Instructions for Pulcet enteric-coated tablets 40 mg No. 14
Composition
active ingredient: pantoprazole;
1 tablet contains pantoprazole sodium sesquihydrate equivalent to pantoprazole 40 mg;
excipients: sodium phosphate, isomalt (E 953), carmellose sodium, crospovidone, sodium stearyl fumarate, hypromellose, povidone, propylene glycol, methacrylate copolymer dispersion, triethyl citrate, simethicone (30% emulsion), titanium dioxide (E 171), iron oxide yellow (E 172).
Dosage form
The film-coated tablets are enteric-coated.
Main physicochemical properties: oval tablets, coated with an enteric coating from light yellow to yellow.
Pharmacotherapeutic group
Medications for the treatment of peptic ulcer and gastroesophageal reflux disease.
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 transformed into the active form in the acidic environment of parietal cells, where it inhibits the H+-K+-ATPase enzyme, i.e. blocks the final stage of hydrochloric acid production in the stomach.
Inhibition is dose-dependent and affects both basal and stimulated acid secretion. Most patients are relieved of heartburn and acid reflux symptoms within 2 weeks. The use of pantoprazole, as with other proton pump inhibitors 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, 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 cells in the stomach (similar to adenomatoid hyperplasia) has been observed during long-term treatment. However, according to studies conducted to date, the formation of neuroendocrine tumor precursor cells (atypical hyperplasia) or neuroendocrine tumors of the stomach 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 completely excluded.
During treatment with antisecretory drugs, serum gastrin levels increase in response to decreased acid secretion. In addition, chromogranin A (CgA) levels increase due to decreased gastric acidity. Elevated CgA levels may interfere with diagnostic tests for neuroendocrine tumors. Available published data suggest that proton pump inhibitor treatment should be discontinued 5–14 days before CgA measurements. This allows CgA levels to return to the normal range, which may be falsely elevated after treatment with proton pump inhibitors (PPIs).
Pharmacokinetics.
Absorption. Pantoprazole is rapidly absorbed and maximum plasma concentrations (Cmax) are reached after a single oral dose of 40 mg. On average, Cmax in serum is reached 2.5 hours after administration at a level of about 2-3 μg/ml; the concentration remains constant after multiple administration. The pharmacokinetic properties do not change after single or repeated administration. In the dose range of 10 to 80 mg, the pharmacokinetics of pantoprazole in plasma remains linear both after oral and intravenous administration. The absolute bioavailability of the tablets has been established to be approximately 77%. Concomitant food intake does not affect the area under the concentration-time curve (AUC) or Cmax in serum, and therefore the 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: 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.
The main part of the metabolites of pantoprazole is excreted in the urine (about 80%), the rest is excreted in the feces. The main metabolite in both serum and urine is desmethylpantoprazole, conjugated with sulfate. The half-life of the main metabolite (about 1.5 hours) is slightly longer than that of pantoprazole.
Special patient groups.
Poor metabolisers. Approximately 3% of Europeans have a 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 AUC was approximately 6 times higher in poor metabolisers than in subjects with a functionally active CYP2C19 enzyme (extensive metabolisers). The mean peak plasma concentration was increased by approximately 60%. These findings do not affect the posology of pantoprazole.
Renal impairment. There are no recommendations for dose reduction when prescribing pantoprazole to patients with 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 patients 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 certain antibiotics.
Duodenal ulcer.
Stomach ulcer.
Zollinger-Ellison syndrome and other hypersecretory pathological conditions.
Contraindication
Hypersensitivity to pantoprazole, benzimidazole derivatives or to any component of the drug.
Interaction with other medicinal products and other types of interactions
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, nelfinavir, 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").
If 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 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. Therefore, monitoring of INR and prothrombin time is necessary in such concomitant use.
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.
Other interactions. Pantoprazole is extensively metabolised in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19 and oxidation by CYP3A4. No clinically significant interactions have been identified with medicinal products also metabolised by these pathways, such as carbamazepine, diazepam, glibenclamide, nifedipine and oral contraceptives containing levonorgestrel and ethinylestradiol.
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.
Pantoprazole can be used concomitantly with antibiotics (clarithromycin, metronidazole, amoxicillin). 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 high-dose pantoprazole therapy 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 the plasma concentration of PPIs that are metabolized by these enzyme systems.
Effects on laboratory test results: False-positive results of some urine screening tests for tetrahydrocannabinol have been reported in patients taking pantoprazole. Alternative testing methods should be considered to confirm positive results.
Application features
Hepatic impairment: Patients with severe hepatic impairment should have their liver enzymes monitored regularly, especially during long-term treatment. If liver enzymes increase, treatment should be discontinued (see section 4.2).
Combination therapy. During combination therapy, the instructions for use of the respective drugs 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 required.
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: In patients with Zollinger-Ellison syndrome and other hypersecretory pathological conditions requiring long-term treatment, pantoprazole, like all antacids, may reduce the absorption of vitamin B12 (cyanocobalamin) due to the occurrence of hypo- and achlorhydria. This should be taken into account in patients with low body weight or in the presence of risk factors for reduced absorption of vitamin B12 during long-term treatment, or in the presence of relevant clinical symptoms.
Long-term treatment: During long-term treatment, especially for more than 1 year, patients should be under the supervision of a physician.
Gastrointestinal infections caused by bacteria. Pantoprazole, like other proton pump inhibitors, may increase the number of bacteria normally present in the upper gastrointestinal tract. Treatment with the drug slightly increases the risk of developing gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or C. difficile.
Hypomagnesemia: Severe hypomagnesemia has been reported in patients receiving proton pump inhibitors (PPIs) such as pantoprazole for at least 3 months, and in most cases for a year. The following serious clinical manifestations of hypomagnesemia may occur and may initially be insidious: fatigue, tetany, delirium, convulsions, dizziness, and ventricular arrhythmias. In the case of hypomagnesemia, the majority of patients improved after magnesium replacement therapy and discontinuation of the PPI.
Bone fractures. Long-term treatment (more than 1 year) with high doses of proton pump inhibitors may slightly increase the risk of hip, wrist and spine fractures, mainly in the elderly or in the presence of other risk factors. Research data indicate that the use of proton pump inhibitors may increase the overall risk of fractures by 10-40%. Some of these may be due to other risk factors. Patients at risk of osteoporosis should be treated according to current clinical guidelines and consume adequate amounts of vitamin D and calcium.
Severe cutaneous adverse reactions. Severe cutaneous adverse reactions have been reported with unknown frequency (see section 4.8) and may be life-threatening or fatal, such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms (DRESS). Patients should be informed of the signs and symptoms of the above-mentioned cutaneous reactions and closely monitored for their development. If signs and symptoms suggestive of these reactions occur, pantoprazole should be discontinued immediately and alternative treatment considered.
Subacute cutaneous lupus erythematosus. The use of proton pump inhibitors has been associated with very rare cases of subacute cutaneous lupus erythematosus. If lesions occur, especially in areas exposed to sunlight, and are accompanied by arthralgia, the patient should immediately consult a doctor who will consider discontinuing Pulcet®. 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.
Effect on laboratory test results. Elevated chromogranin A (CgA) levels may interfere with test results in the diagnosis of neuroendocrine tumors. To avoid this effect, treatment with Pulcet® should be temporarily discontinued for at least 5 days prior to CgA measurement (see section 5.1). If CgA and gastrin levels have not returned to the normal range after initial measurement, repeat measurements should be performed 14 days after discontinuation of proton pump inhibitor treatment.
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 pantoprazole in pregnant women should be avoided.
Breast-feeding. Animal studies have shown excretion of pantoprazole in breast milk. There are insufficient data on the excretion of pantoprazole in human milk, but such excretion has been reported. A risk to the newborn/infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from pantoprazole therapy 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. 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
Pulcet®, gastro-resistant tablets, should be taken whole 1 hour before meals; do not chew or crush the tablets, and drink them with water.
Recommended dosage.
Adults and children aged 12 and over.
Treatment of reflux esophagitis.
The recommended dose is 1 tablet of Pulcet® 40 mg per day. In some cases, the dose can be doubled (2 tablets of Pulcet® 40 mg per day), especially if other drugs for the treatment of reflux esophagitis are ineffective. Reflux esophagitis usually requires 4 weeks to be treated. If this is not enough, healing can be expected within a further 4 weeks.
Adults.
Eradication of H. pylori in combination with two antibiotics.
In adult patients with gastric and duodenal ulcers and positive for H. pylori, eradication of the organism should be achieved using combination therapy. Local data on bacterial resistance and national guidelines for the use and prescription of appropriate antibacterial agents should be taken into account. Depending on susceptibility, the following therapeutic combinations may be used for eradication of H. pylori in adults:
a) 1 tablet of Pulcet® 40 mg 2 times a day
+ 1000 mg of amoxicillin 2 times a day
+ 500 mg of clarithromycin 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 Pulcet® 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 Pulcet® 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 2 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, Pulcet® is prescribed for monotherapy in the dosage indicated below.
Treatment of stomach ulcers.
1 tablet of Pulcet® per day. In some cases, the dose can be doubled (2 tablets of Pulcet® per day), especially if there is no effect from the use of other drugs.
It usually takes 4 weeks to heal a stomach ulcer. If this is not enough, healing can be expected within another 4 weeks.
Treatment of duodenal ulcers.
1 tablet of Pulcet® per day. In some cases, the dose can be doubled (2 tablets of Pulcet® per day), especially if there is no effect from the use of other drugs.
It usually takes 2 weeks for an ulcer to heal. If this is not enough, healing 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 Pulcet® 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 to more than 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. Pulcet® 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. Pulcet® 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.
Pulcet® is indicated for 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 the drug for this age group are limited.
Overdose
Symptoms of overdose in humans are unknown.
Doses up to 240 mg administered intravenously over 2 minutes were well tolerated.
Since pantoprazole is extensively bound to plasma proteins, 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.
Side effects
Adverse reactions were observed in about 5% of patients. The most common adverse reactions were diarrhea and headache (about 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).
The frequency of adverse reactions reported during the post-marketing period cannot be determined and is therefore listed as “not known”.
Within each frequency category, adverse reactions are presented in order of decreasing seriousness.
From the blood and lymphatic system.
Rare: agranulocytosis.
Very rare: leukopenia, thrombocytopenia, pancytopenia.
From the immune system.
Rare: hypersensitivity reactions (including anaphylactic reactions, anaphylactic shock).
From the side of metabolism and metabolism.
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.
From the psychological side.
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.
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.
Not known: microscopic colitis.
On the part of the hepatobiliary system.
Uncommon: increased liver enzymes (transaminases, γ-glutamyltransferase).
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 (toxic epidermal necrolysis), drug reaction with eosinophilia and systemic symptoms (DRESS), 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: tubulointerstitial 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 and/or hypokalemia may be associated with the development of hypomagnesemia (see section "Special warnings and precautions for use").
2 Muscle spasm as a result of electrolyte imbalance.
Reporting of suspected adverse reactions.
Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the link: https://aisf.dec.gov.ua
Expiration date
3 years.
Storage conditions
Store in a dry, dark place at a temperature not exceeding 25 ºС.
Keep out of reach of children.
Packaging
4 tablets in a blister; 1 blister in a cardboard box.
14 tablets in a blister; 1 or 2 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
NOBEL ILACH SANAI VE TJARET A.Sh.
Address
Sankaklar Quarter, Eski Akcakoca Ave., No. 299, 81100 Duzce, Turkey.
