Reflux esophagitis; duodenal ulcer; stomach ulcer; Helicobacter pylori eradication in patients with Helicobacter pylori-associated gastric and duodenal ulcers in combination with appropriate antibiotics; Zollinger-Ellison syndrome and other hypersecretory pathological conditions.
active substance: pantorrazole;
1 tablet contains pantoprazole sodium sesquihydrate equivalent to pantoprazole 20 mg;
Excipients: sodium carbonate anhydrous, mannitol (E 421), crospovidone, hydroxypropylcellulose, calcium stearate, oidragite L30D55, triethyl citrate, sodium lauryl sulfate, titanium dioxide (E 171), iron oxide yellow * e50, E 035.
* Opadry 03F58750 white: hypromellose, titanium dioxide (E 171), polyethylene glycol, talc.
Coated tablets are enteric-coated.
Main physical and chemical properties: oval biconvex tablets, coated with yellow.
Drugs for the treatment of acid-dependent diseases. Proton pump inhibitor.
ATX code A02B CO2.
Mechanism of action.
Pantoprazole is a substituted benzimidazole that inhibits the secretion of hydrochloric acid in the stomach by specifically blocking the proton pumps of parietal cells. Pantoprazole is transformed into the active form in an acidic environment in parietal cells, where it inhibits the enzyme H + -K + -ATPase, ie blocks the final stage of production of hydrochloric acid in the stomach. Inhibition is dose-dependent and inhibits both basal and stimulated acid secretion. Most patients are relieved of symptoms within 2 weeks. The use of pantoprazole, like other proton pump inhibitors (PPIs) and H2-receptor inhibitors, reduces gastric acidity and thus increases gastrin secretion in proportion to the decrease in acidity. Increased gastrin secretion is reversible. Because pantoprazole binds the enzyme distally to the cellular receptor, it can inhibit the secretion of hydrochloric acid regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect of oral and intravenous administration of the drug is the same.
The use of pantoprazole increases the level of gastrin on an empty stomach. With short-term use of the drug, the level of gastrin in most cases does not exceed the upper limit of normal. With long-term treatment, gastrin levels in most cases double. However, their excessive increase occurs only in isolated cases. As a result, sometimes with long-term treatment there is a slight or moderate increase in specific endocrine (ECL) cells in the stomach (similar to adenomatoid hyperplasia). However, according to previous studies, the formation of progenitor cells of neuroendocrine tumors (atypical hyperplasia) or neuroendocrine tumors of the stomach, which were found in animal studies, was not observed in humans. Based on the results of animal studies, the effect of long-term (more than one year) treatment with pantoprazole on endocrine parameters of the thyroid gland cannot be completely ruled out. Against the background of treatment with antisecretory drugs, the level of gastrin in the serum increases in response to a decrease in acid secretion. In addition, due to a decrease in gastric acidity, the level of chromogranin A (CgA) increases. Elevated levels of CgA may affect the results of research in the diagnosis of neuroendocrine tumors. Available published data suggest that PPI treatment should be discontinued within 5 days to 2 weeks before CgA measurements. This allows CgA levels to return to the range of normal values that may be erroneously elevated after PPI treatment.
Pantoprazole is rapidly absorbed, and the maximum plasma concentration is reached after a single oral dose of 20 mg. On average, 2–2.5 hours after ingestion, the maximum concentration in blood serum (Сmax) is reached at the level of about 1–1.5 μg / ml; the concentration remains constant after repeated administration. Pharmacokinetic properties do not change after a single or repeated administration. In the dose range from 10 to 80 mg, the pharmacokinetics of pantoprazole in plasma remain linear with both oral and intravenous administration. It is established that the absolute bioavailability of tablets is about 77%. Concomitant food intake does not affect the area under the plasma-time concentration (AUC) or Cmax curve and, consequently, bioavailability. Simultaneous eating increases only the variability of the latent period.
Pantoprazole is approximately 98% bound to serum proteins. The volume of distribution is about 0.15 l / kg.
The substance is metabolized almost exclusively in the liver. The major metabolic pathway is demethylation by CYP2C19 followed by sulfate conjugation; other metabolic pathways include oxidation by CYP3A4.
The terminal half-life is about 1 hour and the clearance is 0.1 l / h / kg. There have been several cases of delayed withdrawal. Due to the specific binding of pantoprazole to proton pumps of parietal cells, the half-life does not correspond to a much longer duration of action (inhibition of acid secretion).
The main part of pantoprazole metabolites is excreted in the urine (about 80%), the rest is excreted in the feces. The main metabolite in both serum and urine is sulfate-conjugated desmethylpantoprazole. The half-life of the major metabolite (about 1.5 hours) is not much longer than the half-life of pantoprazole.
Special groups of patients
About 3% of Europeans have low functional activity of the enzyme CYP2C19; they are called slow metabolizers. In such individuals, the metabolism of pantoprazole is probably mainly catalyzed by the enzyme CYP3A4. Following a single dose of 40 mg pantoprazole, the AUC was approximately 6-fold higher in slow metabolisers than in subjects with the functionally active enzyme CYP2C19 (fast metabolisers). The average peak plasma concentration increased by approximately 60%. These results do not affect the dosage of pantoprazole.
There are no dose reduction recommendations for pantoprazole in patients with impaired renal function (including dialysis patients). As in healthy volunteers, the half-life of pantoprazole in them is short. Only very small amounts of pantoprazole are dialyzed. Despite the fact that the main metabolite has a moderately long half-life (2-3 hours), excretion is still rapid, so accumulation does not occur.
Although in patients with liver cirrhosis (Child-Pugh classes A and B) the half-life increases to 3–6 hours and the AUC increases 3–5-fold, the Cmax increases only slightly, 1.3-fold compared to such in healthy volunteers.
A slight increase in AUC and Cmax in elderly volunteers compared to the corresponding values in younger volunteers is also not clinically relevant.
Following a single oral dose of 20 or 40 mg pantoprazole, AUC and Cmax in children 5 to 16 years of age were within the corresponding range in adults.
Following a single intravenous administration of pantoprazole at doses of 0.8 or 1.6 mg / kg in children aged 2 to 16 years, there was no significant association between pantoprazole clearance and the patient’s age or body weight. The AUC and volume of distribution corresponded to data from adult studies.
Adults and children from 12 years old.
Symptomatic treatment of gastroesophageal reflux disease.
Long-term treatment and prevention of recurrence of reflux esophagitis.
Prevention of gastric and duodenal ulcers caused by non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk who should use NSAIDs for a long time.
Hypersensitivity to the active substance or to any component of the drug, to benzimidazole derivatives.
Interaction with other medicinal products and other forms of interaction
Drugs whose absorption depends on pH. Due to the complete and long-term inhibition of hydrochloric acid secretion, pantoprazole may affect the absorption of drugs for which gastric pH is an important factor in their bioavailability (eg, some antifungal drugs such as ketoconazole, itraconazole, posaconazole, or other drugs such as erlot).
HIV protease inhibitors. Co-administration 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.
If co-administration of HIV protease inhibitors with PPIs cannot be avoided, close clinical monitoring (eg viral load) is recommended. The daily dose of pantoprazole should not exceed 20 mg. Dose adjustment of HIV protease inhibitors may be required.
Coumarin anticoagulants (phenprocoumon and warfarin)
Co-administration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon or MNI (International Normalized Index). However, elevations in IOP and prolongation of prothrombin time have been reported in patients receiving PPI and warfarin or phenprocoumon concomitantly. Elevated MRI and prolonged prothrombin time can lead to abnormal bleeding and even death. In the case of such co-administration, it is necessary to monitor the MRI and prothrombin time.
Concomitant use of high doses of methotrexate (eg, 300 mg) and PPIs has been shown to increase blood levels of methotrexate in some patients. Patients taking high doses of methotrexate, such as cancer or psoriasis, are advised to temporarily discontinue pantoprazole.
Pantoprazole is extensively metabolized in the liver through the cytochrome P450 enzyme system. The major metabolic pathway is demethylation by CYP2C19 and other metabolic pathways, including oxidation by the enzyme CYP3A4. There are no data on clinically significant interactions between pantoprazole and drugs that are also metabolised by these routes (carbamazepine, diazepam, glibenclamide, nifedipine, oral contraceptives containing levonorgestrel and ethinyl estradiol).
The interaction of pantoprazole with other drugs that are metabolized through the same enzyme system cannot be ruled out.
The results of a number of studies on possible interactions indicate that pantoprazole does not affect the metabolism of active substances metabolised by CYP1A2 (eg, caffeine, theophylline), CYP2C9 (eg, piroxicam, diclofenac, naproxen), CYP2D2 (eg, metopro (eg, ethanol) does not affect the p-glycoprotein associated with digoxin absorption.
No interaction with co-administered antacids was detected.
Studies have been conducted to study the interaction of pantoprazole with certain antibiotics (clarithromycin, metronidazole, amoxicillin). No clinically significant interactions between these drugs were detected.
Drugs that inhibit or induce CYP2C19. CYP2C19 inhibitors, such as fluvoxamine, may increase the systemic effects of pantoprazole. Dose reduction should be considered for patients receiving long-term high-dose pantoprazole therapy and for patients with hepatic impairment. Inducers of enzymes that affect CYP2C19 and CYP3A4, such as rifampicin and St. John’s wort (Hypericum perforatum), may reduce the plasma concentrations of PPIs that are metabolized through these enzyme systems.
Features of application
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 (see section “Method and Dosage”).
Concomitant use with NSAIDs
The use of Zolopent®, 20 mg tablets, for the prevention of gastric and duodenal ulcers caused by NSAIDs should be limited for a long time in patients who are prone to frequent exacerbations of gastric and duodenal ulcers.
The assessment of the level of risk is made taking into account individual risk factors, including age (> 65 years), history of gastric or duodenal ulcer, as well as gastrointestinal bleeding.
Malignant neoplasms of the stomach
Symptomatic response to pantoprazole may mask the symptoms of gastric malignancies and delay their diagnosis. In the presence of anxious symptoms (for example, in the case of significant weight loss, intermittent vomiting, dysphagia, vomiting of blood, anemia, melena), as well as in the presence or suspicion or presence of gastric ulcer, the presence of a malignant process should be ruled out. If symptoms persist with adequate treatment, additional examination should be performed.
HIV protease inhibitors
Co-administration 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 forms of interaction”).
Absorption of vitamin B12
Pantoprazole may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- and achlorhydria. This should be considered in the case of reduced body weight in patients or the presence of risk factors for reduced absorption of vitamin B12 during long-term treatment, or the presence of relevant clinical symptoms.
During long-term treatment, especially more than one year, patients should be under regular medical supervision.
Infections of the gastrointestinal tract 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.
Cases of severe hypomagnesemia have been observed in patients receiving PPIs, such as pantoprazole, for at least three months, and in most cases within 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 patients’ condition improved after replacement therapy with magnesium drugs and discontinuation of PPIs.
Patients in need of long-term therapy, or patients taking PPIs concomitantly with digoxin or drugs that may cause hypomagnesemia (eg diuretics), should have their magnesium levels measured before and periodically during treatment with PPIs.
Long-term treatment (more than one year) with high doses of PPIs may moderately increase the risk of hip, wrist and spine fractures, especially in the elderly or in the presence of other risk factors. It is known that the use of PPIs can increase the overall risk of fractures by 10-40%. Some of them may be due to other risk factors. Patients at risk for osteoporosis should receive treatment in accordance with current clinical guidelines and consume sufficient amounts of vitamin D and calcium.
Subacute cutaneous lupus erythematosus
The use of PPIs is 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 physician who will consider discontinuing pantoprazole. The occurrence of subacute cutaneous lupus erythematosus in patients during previous PPI therapy may increase the risk of its development with other PPIs.
Influence on the results of laboratory tests.
Elevated levels of chromogranin A (CgA) may affect the results of research in the diagnosis of neuroendocrine tumors. To avoid this effect, pantoprazole treatment should be temporarily discontinued at least 5 days before the CgA assessment (see Pharmacodynamics). If CgA and gastrin levels do not return to normal after the initial measurement, repeated measurements should be performed 14 days after discontinuation of PPI treatment.
Use during pregnancy or breastfeeding
Available data on the use of pantoprazole in pregnant women (approximately 300-1000 reports of pregnancy outcomes) indicate the absence of embryonic or feto-neonatal toxicity of the drug. Reproductive toxicity was observed in animal studies. As a precautionary measure, pantoprazole should be avoided in pregnant women.
Animal studies have shown excretion of pantoprazole in breast milk. There are insufficient data on the excretion of pantoprazole in human breast milk, but such excretion has been reported. The risk to newborns / infants cannot be ruled out. The decision to discontinue breast-feeding or to discontinue / abstain from pantoprazole therapy should be made taking into account the benefit of breast-feeding to the child and the benefit of pantoprazole therapy to the woman.
Pantoprazole did not impair fertility in animal studies.
Ability to influence the speed of reaction when driving a car or other machinery
Pantoprazole has no or very little effect on the speed of reaction when driving or operating machinery. Possible development of adverse reactions such as dizziness and visual disturbances should be considered (see Adverse Reactions). In such cases it is not necessary to drive vehicles or work with other mechanisms.
Method of application and dosage
Zolopent®, 20 mg, tablets should be taken 1 hour before meals whole, not chewed or crushed, washed down with water.
Adults and children from 12 years old.
Symptomatic treatment of gastroesophageal reflux disease.
The recommended dose is 20 mg (1 tablet) of Zolopent® per day. The symptoms of heartburn usually go away within 2-4 weeks. If this period is not enough, treatment is continued for the next 4 weeks. After the disappearance of symptoms, the recurrence of symptoms can be controlled by using, if necessary, 20 mg of the drug once a day, taking 1 tablet when necessary. The transition to long-term therapy should be considered in the event that satisfactory control of symptoms is not provided during on-demand therapy.
Long-term treatment and prevention of recurrence of reflux esophagitis.
For long-term treatment, the maintenance dose is 20 mg (1 tablet) of Zolopent® per day, with exacerbation of the disease may increase the dose to 40 mg per day. In this case, it is recommended to take Zolopent® 40 mg tablets. After elimination of recurrence the dose can be reduced again to 20 mg of drug a day.
Prevention of gastric and duodenal ulcers caused by non-selective anti-inflammatory drugs (NSAIDs) in patients at risk who should take NSAIDs for a long time.
The recommended dose is 20 mg (1 tablet) of Zolopent® per day.
Patients with severe hepatic impairment should not exceed a dose of 20 mg (1 tablet) per day.
Patients with impaired renal function do not require dose adjustment.
Elderly patients do not require dose adjustment.
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.
Symptoms of overdose are unknown.
Doses up to 240 mg administered intravenously over 2 minutes were well tolerated. Because pantoprazole is extensively protein bound, it is not a dialysis drug that can be easily removed by dialysis.
In case of overdose with the appearance of clinical signs of intoxication, symptomatic and supportive therapy is used. There are no recommendations for specific therapy.
From the blood and lymphatic system:
agranulocytosis, leukopenia, thrombocytopenia, pancytopenia.
From the immune system:
hypersensitivity reactions (including anaphylactic reactions, anaphylactic shock).
Metabolism and metabolic disorders:
hyperlipidemia and elevated lipids (triglycerides, cholesterol); weight change, hyponatremia, hypomagnesemia (see section “Peculiarities of use”), hypocalcemia1, hypokalemia.
From the psyche:
sleep disorders, depression (including exacerbations), disorientation (including exacerbations), 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.
From the eyes:
visual disturbances / blurred vision.
From the digestive tract:
diarrhea, nausea, vomiting, bloating, constipation, dry mouth, abdominal pain and discomfort, polyps from the fundus glands (benign).
From the hepatobiliary system:
increased levels of liver enzymes (transaminases, g-HT), increased bilirubin, hepatocyte damage, jaundice, hepatocellular insufficiency.
Skin and subcutaneous tissue disorders:
skin rash, exanthema, pruritus, urticaria, angioneurotic edema, Stevens-Johnson syndrome, Lyell’s syndrome, erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus.
From the musculoskeletal system and connective tissue:
fractures of the thigh, wrist or spine
(see section “Peculiarities of use”), arthralgia, myalgia, muscle spasm2.
From the kidneys and urinary system:
interstitial nephritis (with possible development of renal failure).
From the reproductive system and mammary glands:
asthenia, fatigue, malaise, fever, peripheral edema.
1 Hypocalcemia simultaneously with hypomagnesemia.
2 Muscle spasm as a consequence of electrolyte imbalance.
Store in the original package at a temperature not exceeding 25 ° C.
Keep out of reach of children.
14 tablets in a blister. 1 blister in a cardboard package.