Instructions for use Zolopent film-coated tablets 40 mg No. 14
Composition
active ingredient: pantoprazole;
1 tablet contains pantoprazole sodium sesquihydrate equivalent to pantoprazole 40 mg;
excipients: sodium carbonate anhydrous, mannitol (E 421), crospovidone, hydroxypropylcellulose, calcium stearate, methacrylate copolymer dispersion, triethyl citrate, sodium lauryl sulfate, titanium dioxide (E 171), iron oxide yellow (E 172), talc, Opadry 03F58750 white*.
* Opadry 03F58750 white: hypromellose, titanium dioxide (E 171), polyethylene glycol, talc.
Dosage form
The film-coated tablets are enteric-coated.
Main physicochemical properties: oval biconvex tablets, coated with a yellow shell.
Pharmacotherapeutic group
Drugs for the treatment of acid-dependent diseases. 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 stage of hydrochloric acid production in the stomach. Inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, symptoms resolve within 2 weeks. The use of pantoprazole, like 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 usually do not exceed the upper limit of normal. In long-term treatment, gastrin levels are usually doubled. Excessive increases occur only in isolated cases. As a result, a slight to moderate increase in specific endocrine (ECL) cells in the stomach (similar to adenomatoid hyperplasia) is sometimes observed during long-term treatment. However, according to 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 thyroid endocrine parameters cannot be completely excluded.
During treatment with antisecretory drugs, serum gastrin levels increase in response to decreased acid secretion. In addition, chromogranin A (CgA) levels increase due to decreased gastric acidity. Elevated CgA levels may interfere with diagnostic tests for neuroendocrine tumors. Available published data suggest that PPI treatment should be discontinued for 5 days to 2 weeks before CgA measurements. This allows CgA levels, which may be falsely elevated after PPI treatment, to return to the normal range.
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 of about 2–3 μg/ml is reached 2.5 hours after administration; 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 remain linear both after oral and intravenous administration. The absolute bioavailability of pantoprazole in tablets has been found to be about 77%. Concomitant food intake does not affect the area under the concentration-time curve (AUC) or Cmax, 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. 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 the half-life of pantoprazole.
Special patient groups.
Poor metabolisers. Approximately 3% of Europeans have a low functional activity of the CYP2C19 enzyme, and are referred to as poor metabolisers. In these individuals, the metabolism of pantoprazole is likely to be 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 volunteers, 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, 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 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 or to any component of the drug, to benzimidazole derivatives.
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 PPIs cannot be avoided, close clinical monitoring (e.g. viral load) is recommended. The daily dose of pantoprazole should not exceed 20 mg. Dose adjustment of HIV protease inhibitors may be necessary.
Coumarin anticoagulants (phenprocoumon and warfarin). Concomitant use of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon or the international normalized ratio (INR). 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, 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 methotrexate blood levels in some patients. Patients receiving high doses of methotrexate, e.g. for cancer or psoriasis, are advised to temporarily discontinue pantoprazole treatment.
Interactions of pantoprazole with other drugs metabolized by this 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 interactions with concomitantly administered antacids were identified.
Studies have been conducted to study the interaction of pantoprazole with certain concomitantly administered antibiotics (e.g. 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 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 should be discontinued (see section 4.2).
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 (e.g. 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, as with 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 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 one year, patients should be under regular medical supervision.
Gastrointestinal infections caused by bacteria. Treatment with pantoprazole 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. Serious clinical manifestations of hypomagnesemia may occur and may initially be insidious, including fatigue, tetany, delirium, convulsions, dizziness, and ventricular arrhythmias. In the case of hypomagnesemia, most patients improved after magnesium replacement therapy and discontinuation of the PPI.
Patients requiring long-term therapy or patients taking PPIs concomitantly with digoxin or drugs that may cause hypomagnesemia (e.g., diuretics) should have their magnesium levels measured before starting PPI treatment and periodically during treatment.
Subacute cutaneous lupus erythematosus. The use of PPIs has been associated with very rare cases of subacute cutaneous lupus erythematosus. If lesions occur, especially in areas exposed to sunlight, and are accompanied by arthralgia, the patient should immediately consult a doctor who will consider discontinuing pantoprazole. The occurrence of subacute cutaneous lupus erythematosus in patients on previous PPI therapy may increase the risk of its development with other PPIs.
Impact on laboratory test results.
Elevated chromogranin A (CgA) levels may interfere with the results of diagnostic tests for neuroendocrine tumours. To avoid this interference, pantoprazole treatment should be temporarily discontinued for at least 5 days before CgA measurements (see section 5.2). If CgA and gastrin levels have not returned to the normal range after initial measurement, repeat measurements should be performed 14 days after discontinuation of PPI treatment.
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 feto-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 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 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
Zolopent®, film-coated, enteric-coated tablets, 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.
Treatment of reflux esophagitis.
The recommended dose is 1 tablet of Zolopent® 40 mg per day. In some cases, the dose can be doubled (2 tablets of Zolopent® 40 mg per day), especially if other drugs for the treatment of reflux esophagitis are ineffective.
Treatment for reflux esophagitis usually lasts 4 weeks. If this is not enough, recovery 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 prescription and use of appropriate antibacterial agents should be taken into account. Depending on the susceptibility of microorganisms, the following therapeutic combinations may be prescribed for the eradication of H. pylori in adults:
a) 1 tablet of Zolopent® 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 Zolopent® 40 mg 2 times a day + 400–500 mg of metronidazole (or 500 mg of tinidazole) 2 times a day + 250–500 mg of clarithromycin 2 times a day;
c) 1 tablet of Zolopent® 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 Zolopent® 40 mg should be taken in the evening 1 hour before a meal. The duration of treatment is 7 days and may be extended for another 7 days with a total duration of treatment not exceeding 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, Zolopent® 40 mg is used for monotherapy in the dosage indicated below.
Treatment of stomach ulcers.
1 tablet of Zolopent® 40 mg per day. In some cases, the dose can be doubled (2 tablets of Zolopent® 40 mg per day), especially if there is no effect from the use of other drugs.
Treatment for stomach ulcers usually lasts 4 weeks. If this is not enough, healing of the ulcer can be expected within another 4 weeks.
1 tablet of Zolopent® 40 mg per day. In some cases, the dose can be doubled (2 tablets of Zolopent® 40 mg per day), especially if there is no effect from the use of other drugs.
Treatment for duodenal ulcers usually lasts 2 weeks. 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 Zolopent® 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 (1 tablet of Zolopent® 20 mg). Patients with moderate and severe hepatic impairment should not use Zolopent® for the 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.
Patients with renal impairment. No dose adjustment is required for patients with renal impairment. Patients with renal impairment should not use Zolopent® for the eradication of H. pylori in combination therapy, as there is currently no data on the efficacy and safety of use in this category of patients.
Elderly patients do not require dose adjustment.
Children
Zolopent® 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 the safety and efficacy of pantoprazole in this age group are limited.
Overdose
Symptoms of overdose are unknown.
Doses up to 240 mg administered intravenously over 2 minutes have been well tolerated. Since pantoprazole is extensively protein bound, it is not a drug that can be readily dialyzed.
In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy is used. There are no specific therapy recommendations.
Adverse reactions
From the blood and lymphatic system: agranulocytosis, leukopenia, thrombocytopenia, pancytopenia.
Immune system disorders: hypersensitivity reactions (including anaphylactic reactions, anaphylactic shock).
Metabolism and metabolic disorders: hyperlipidemia and increased lipid levels (triglycerides, cholesterol); weight change, hyponatremia, hypomagnesemia (see section "Special warnings and precautions for use"), hypocalcemia1, hypokalemia.
Psychiatric: sleep disorders, depression (including exacerbation), disorientation (including exacerbation), 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: headache, dizziness, taste disturbances, paresthesia.
On the part of the organs of vision: visual impairment/blurred vision.
On the part of the digestive tract: diarrhea, nausea, vomiting, bloating, constipation, dry mouth, abdominal pain and discomfort, fundic gland polyps (benign).
On the part of the hepatobiliary system: increased levels of liver enzymes (transaminases, g-GT), increased levels of bilirubin, hepatocyte damage, jaundice, hepatocellular insufficiency.
Skin and subcutaneous tissue disorders: skin rash, exanthema, pruritus, urticaria, angioedema, 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: fractures of the hip, wrist or spine (see section "Special warnings and precautions for use"), arthralgia, myalgia, muscle spasm2.
On the part of the kidneys and urinary system: interstitial nephritis (with possible development of renal failure).
Reproductive system and breast disorders: gynecomastia.
General disorders: asthenia, fatigue, malaise, fever, peripheral edema.
1 Hypocalcemia concomitant with hypomagnesemia.
2 Muscle spasm due to electrolyte imbalance.
Expiration date
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
14 tablets in a blister; 1 blister in a cardboard box.
10 tablets in a blister; 3 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
"KUSUM FARM" LLC.
Location of the manufacturer and address of its place of business
40020, Ukraine, Sumy region, Sumy city, Skryabina st., 54.
