Composition:
1 tablet 40 mg Core: Active ingredient: Pantoprazole sodium sesquihydrate 45.10 mg (equivalent to Pantoprazole 40.00 mg) Excipients: mannitol, crospovidone, sodium carbonate, sorbitol, calcium stearate Film sheath: Hypromellose, povidone K-25, titanium dioxide (E171), iron dye oxide yellow (E172), propylene glycol, methacrylic acid and ethyl acrylate copolymer (1: 1), 30% dispersion1, talc, macrogol-6000 1
The polymer dispersion contains 0.7% sodium lauryl sulfate and 2.3% polysorbate-80 as emulsifiers.
Pharmacodynamics:
Proton pump inhibitor (H + / K + -ATPase). It blocks the final stage of hydrochloric acid secretion, regardless of the nature of the stimulus.
Pantoprazole is a substituted benzimidazole that inhibits the secretion of hydrochloric acid in the stomach through specific blockade of proton pumps of parietal cells. Pantoprazole transforms into its active form under acidic conditions in parietal cells, where it inhibits the activity of the H + / K + -ATPase enzyme, i.e., it blocks the final stage of the formation of hydrochloric acid in the stomach. The suppression of activity is dose-dependent, and as a result, both basal and stimulated acid secretion are reduced.
During treatment with pantoprazole, as with other proton pump inhibitors (IPIs) and H2 receptor blockers, acidity in the stomach decreases and, therefore, gastrin levels increase in proportion to the decrease in acidity. Increased gastrin levels are reversible. The concentration of chromogranin A (CgA) also increases due to a decrease in gastric acidity. An increased concentration of CgA may interfere with the diagnosis of neuroendocrine tumors.
Published data indicate that the use of PPI should be stopped in the range from 5 days to 2 weeks before determining the concentration of CgA, which allows the use of data on the concentration of CgA, which can be falsely increased during therapy of PPI, and returns to the normal range after its cancellation .
Since pantoprazole binds the enzyme distally to the cellular receptor, it can inhibit the secretion of hydrochloric acid regardless of stimulation with other substances (acetylcholine, histamine, gastrin). The effect with oral and intravenous administration of the drug is the same.
Antisecretory activity After the first oral administration of 20 mg of Nolpaza®, a decrease in gastric juice secretion by 24% occurs after 2.5-3.5 hours and by 26% after 24.5-25.5 hours. After oral administration of pantoprazole once daily within 7 days, its antisecretory activity, measured 2.5-3.5 hours after administration, increases to 56%, and after 24.5-25.5 hours - up to 50%.
With duodenal ulcer associated with Helicobacter pylori, a decrease in gastric secretion increases the sensitivity of microorganisms to antibiotics. Does not affect gastrointestinal motility. Secretory activity is normalized 3-4 days after the end of the dose.
Compared to other PPIs, Nolpaza® has greater chemical stability at a neutral pH, and lower potential for interaction with the liver oxidase system, which depends on the cytochrome P450 system. Therefore, no clinically significant interaction was observed between the drug Nolpaza® and many other drugs.
Pharmacokinetics:
Pantoprazole is rapidly absorbed after oral administration. The maximum concentration in plasma (Cmax) for oral administration is reached after the first dose of 20 mg or 40 mg.
Cmax of about 1.0-1.5 μg / ml is achieved on average about 2.0-2.5 hours after taking a dose of 20 mg and about 2.0-3.0 μg / ml - 2.5 hours after taking doses of 40 mg. Cmax remains constant after repeated administration of the drug. The pharmacokinetics of pantoprazole after a single and multiple use is the same.
In the dose range of 10-80 mg, the pharmacokinetics of pantoprazole in the blood plasma remains linear with both oral and intravenous administration. The absolute bioavailability of pantoprazole tablets is about 77%. Shared food does not affect the area under the concentration-time curve (AUC), Cmax in serum and, accordingly, bioavailability.
When taken together with food, the time of onset of the drug may vary. The binding of pantoprazole to plasma proteins is 98%. The volume of distribution is 0.15 l / kg. Metabolized mainly in the liver. The main metabolic pathway is demethylation using the CYP2C19 isoenzyme followed by sulfate conjugation.
Other metabolic pathways include oxidation with the CYP3A4 isoenzyme. The final half-life (T1 / 2) is about 1 hour, and the clearance is about 0.1 l / h / kg. Due to the specific binding of pantoprazole to proton pumps of parietal cells, the half-life does not correlate with a much longer duration of action (inhibition of acid secretion).
The main route of excretion is through the kidneys (about 80%) in the form of pantoprazole metabolites, the rest is excreted with feces. The main metabolite in blood plasma and urine is desmethyl pantoprazole conjugated to sulfate. T1 / 2 of the main metabolite is about 1.5 hours, which slightly exceeds the half-life of pantoprazole. In individuals with low functional activity of the CYP2C19 isoenzyme (slow metabolizers), pantoprazole metabolism is probably carried out mainly by the CYP3A4 isoenzyme.
After a single dose of pantoprazole 40 mg was taken, the average area under the concentration-time curve was approximately 6 times larger in slow metabolizers than in individuals with functionally active CYP2C19 isoenzyme (fast metabolizers).
The average values of Cmax in plasma are increased by about 60%. These features do not affect the dosage of pantoprazole. When pantoprazole is used in patients with impaired renal function (including patients on hemodialysis), a dose reduction is not required. As with healthy volunteers, T1 / 2 pantoprazole is short. Only a very small fraction of the drug is dialyzed.
Despite the moderately long T1 / 2 of the main metabolite (2-3 hours), its excretion occurs rather quickly, and therefore, accumulation does not occur. In patients with liver cirrhosis (Child-Pugh classification classes A and B), T1 / 2 time increases to 3-6 hours, AUC values increase 3-5 times, Cmax in serum increases slightly, only 1.3 times in comparison with healthy volunteers, when pantoprazole is used in a dosage of 20 mg and, accordingly, when pantoprazole is used in a dosage of 40 mg, T1 / 2 time increases to 7-9 hours, AUC values increase 5-7 times, Cmax in serum increases by 1, 5 times in comparison with that of healthy volunteers. A slight increase in AUC and Cmax in elderly patients compared to those in younger patients is not clinically significant.
Side effects:
In approximately 5% of patients, development of adverse drug reactions (NLR) can be expected. The most common NLRs are diarrhea and headache, which develop in approximately 1% of patients. The following are the NLRs recorded with pantoprazole, classified according to the frequency of occurrence as follows: • very often (? 1/10) • often (? 1/100 and <1/10) • infrequently (? 1/1000 and <1 / 100) • rarely (? 1/10 000 and <1/1000) • very rarely (<1/10 000) • frequency is unknown (it is impossible to estimate based on available data).
For adverse reactions identified during post-registration use of the drug, it is impossible to apply any category of frequency of occurrence, and therefore they are indicated as “frequency unknown”. Within each frequency group, adverse reactions are presented in decreasing order of severity.
Disorders from the blood and lymphatic system: rarely: agranulocytosis; very rarely: thrombocytopenia, leukopenia, pancytopenia. Immune system disorders: rarely: hypersensitivity (including anaphylactic reactions, including anaphylactic shock). Disorders from metabolism and nutrition: rarely: hyperlipidemia and increased concentration of lipids (triglycerides, cholesterol) in blood plasma, change in body weight; frequency unknown: hyponatremia, hypomagnesemia, hypocalcemia in combination with hypomagnesemia, hypokalemia. Mental disorders: infrequently:
sleep disturbance; rarely: depression (including exacerbation of existing disorders); very rarely: disorientation (including exacerbation of existing disorders); the frequency is unknown: hallucinations, confusion (especially in predisposed patients, as well as a possible exacerbation of symptoms if they exist before using the drug). Violations of the nervous system: infrequently: headache, dizziness; rarely: dysgeusia (taste disorder); frequency unknown: paresthesia.
Disorders of the organ of vision: rarely: impaired vision / blurred vision. Violations of the gastrointestinal tract: often: benign polyps of the bottom of the stomach; infrequently: diarrhea, nausea / vomiting, bloating and flatulence, constipation, dry mucous membranes of the oral cavity, pain and discomfort in the abdomen.
Disorders from the liver and biliary tract: infrequently: increased activity of "liver" enzymes (transaminases,? -Glutamyltransferase) in blood plasma; rarely: increased plasma bilirubin concentration; frequency unknown: hepatocellular damage, jaundice, hepatocellular failure.
Violations of the skin and subcutaneous tissues: infrequently: skin rash / exanthema / rash, skin itching; rarely: urticaria, angioedema; frequency unknown: Stevens-Johnson syndrome, Lyell syndrome, erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (PKKV). Violations of the musculoskeletal and connective tissue: infrequently: a fracture of the neck of the femur, bones of the wrist or spine; rarely: arthralgia, myalgia; frequency unknown: muscle spasm as a result of electrolyte imbalance.
Disorders from the kidneys and urinary tract: frequency unknown: interstitial nephritis (with possible progression to renal failure). Disorders from the genitals and mammary gland: rarely: gynecomastia. General disorders and disorders at the injection site: infrequently: asthenia, excessive fatigue and malaise; rarely: fever, peripheral edema.
Special conditions:
Before starting treatment with Nolpaza®, the possibility of a malignant neoplasm should be excluded, since the drug can mask the symptoms and delay the correct diagnosis. Patients should consult a doctor if they have to undergo an endoscopy or urea breath test. Patients should consult a physician if there are the following cases:
• Unintentional weight loss, anemia, gastrointestinal bleeding, swallowing disorder, persistent vomiting or vomiting of blood. In these cases, taking the drug can partially alleviate the symptoms and delay the correct diagnosis;
• previous surgery on the gastrointestinal tract or stomach ulcer;
• continuous symptomatic treatment of dyspepsia and heartburn for 4 weeks or more;
• liver diseases, including jaundice and liver failure;
• other serious diseases that worsen general health. Patients over 55 years of age with new or recently changed symptoms should consult a doctor.
Gastrointestinal infections caused by bacteria Pantoprazole, like other PPIs, can increase the number of bacteria that are usually present in the upper gastrointestinal tract. Treatment of PPI may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or C. difficile.
Effect on the absorption of vitamin B12 In patients with Zollinger-Ellison syndrome and other pathological hypersecretory conditions requiring long-term treatment, pantoprazole, like all drugs that block acid secretion, can reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be taken into account in patients with a reduced supply of vitamin B12 in the body or with risk factors for vitamin B12 malabsorption during prolonged therapy or in the presence of appropriate clinical symptoms. Long-term therapy With long-term therapy, especially for periods longer than 1 year, patients should be under regular medical supervision.
Concomitant use with atazanavir Concomitant use of atazanavir with PPI is not recommended. If the use of atazanavir with IIT is necessary, careful clinical monitoring (for example, measuring the viral load) should be carried out in combination with an increase in the dose of atazanavir to 400 mg with the use of 100 mg of ritonavir. Do not exceed the daily dose of pantoprazole 20 mg (see section "Interaction with other drugs").
Hypomagnesemia Cases of severe hypomagnesemia have been reported in patients receiving PPI, such as pantoprazole, for at least 3 months, and in most cases, for a year. Serious manifestations of hypomagnesemia, such as increased fatigue, tetany, delirium, cramps, dizziness, and ventricular arrhythmia, can begin unnoticed and can be skipped. In most cases, the condition of patients improves after substitution therapy with magnesium and discontinuation of treatment of PPI.
Patients requiring long-term therapy or taking PPI in combination with digoxin or drugs that can cause hypomagnesemia (for example, diuretics) need to determine the plasma magnesium content before starting PPI treatment and periodically during treatment. Bone fractures
Fractures of bones Long-term treatment (more than 1 year) with high doses of PPI may slightly increase the risk of fractures of the hip, wrist and spine, mainly in the elderly or in the presence of other risk factors.
Observational studies suggest that IDUs may increase the overall risk of fractures by 10–40%. Some of them may be due to other risk factors. Patients at risk of developing osteoporosis should receive treatment in accordance with current clinical guidelines and consume enough vitamin D and calcium.
Subacute cutaneous lupus erythematosus Application of PPI can cause PKKV in very rare cases. In the event of foci of skin lesions, especially in areas exposed to sun exposure, accompanied by arthralgia, the patient should immediately seek medical help. The doctor should consider discontinuing the drug Nolpaza ?.
PKKV due to prior therapy with a proton pump inhibitor may increase the risk of developing PKKV with subsequent therapy with other PPIs. Liver failure In patients with severely impaired liver function, it is necessary to regularly monitor the activity of “liver” enzymes during treatment with pantoprazole, especially with prolonged use of the drug. With an increase in the activity of “liver” enzymes, therapy should be discontinued.
Combination therapy In the case of combination therapy, it is necessary to read the instructions for medical use for the drugs used in combination. Influence on the ability to drive vehicles, mechanisms. One should refrain from driving vehicles and other mechanisms that require increased attention, as dizziness and visual impairment are possible.
Indications:
• Gastroesophageal reflux disease (GERD), including erosive-ulcerative reflux esophagitis and symptoms associated with GERD: heartburn, acidic regurgitation, pain when swallowing.
• Peptic ulcer of the stomach and duodenum (in the acute phase), erosive gastritis (including those associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs)).
• Zollinger-Ellison syndrome.
• Eradication of Helicobacter pylori in combination with antibacterial agents.
Contraindications:
• Hypersensitivity to any of the components of the drug, as well as to substituted benzimidazoles.
• Dyspepsia of neurotic origin.
• Concomitant use with atazanovir.
• Children's age up to 18 years.
• Pregnancy, the period of breastfeeding. • Patients with congenital fructose intolerance are not recommended to take the drug Nolpaza®, because it includes sorbitol.
With caution, liver failure, risk factors for deficiency of cyanocobalamin (vitamin B12) (especially against the background of hypo- and achlorhydria).
Use during pregnancy and during breastfeeding Pregnancy As a precaution, it is necessary to exclude the use of Nolpaza® during pregnancy.
The period of breastfeeding Due to insufficient information on the use of the drug Nolpaza® in women during the period of breastfeeding, the potential risk for newborns and infants who are breastfed cannot be ruled out. In this regard, it is necessary to make a decision to stop breastfeeding or to cancel / suspend treatment with Nolpaza®. Fertility
There are no data on the effects of Nolpaza® on human fertility. Preclinical studies have shown no effect on male or female fertility.
Drug Interactions:
The simultaneous use of other proton pump inhibitors or H2-histamine receptor blockers is not recommended without consulting a doctor. The effect of pantoprazole on the absorption of other drugs Due to the deep and prolonged suppression of the secretion of gastric juice, pantoprazole can reduce the absorption of drugs whose bioavailability depends on the pH of the stomach (for example, some azole antifungal drugs, such as ketoconazole, itraconazole, posaconazole, and other drugs such like erlotinib). Drugs for the treatment of HIV infection (atazanavir)
The simultaneous use of atazanavir and other drugs for the treatment of HIV infection, the absorption of which depends on pH, with PPI can lead to a significant decrease in the bioavailability of these drugs for the treatment of HIV infection and may affect the effectiveness of these drugs preparations. The simultaneous use of PPI and atazanavir is not recommended. In the event that the simultaneous use of HIV protease inhibitors and IDUs is still necessary, it is recommended to conduct careful clinical monitoring (for example, determination of viral load).
The dose of pantoprazole should not exceed 20 mg per day. A dose adjustment of the HIV protease inhibitor may also be required. Indirect anticoagulants (fenprocoumone or warfarin) Despite the fact that in clinical pharmacokinetic studies there was no interaction with the simultaneous use of pantoprazole with fenprocoumone or warfarin, several individual cases of changes in the international normalized ratio (INR) were recorded in the post-registration period.
Therefore, it is recommended to control prothrombin time / INR at the beginning and at the end of therapy, as well as during irregular use of pantoprazole. Methotrexate With the simultaneous use of high doses of methotrexate (for example, 300 mg) and PPI, the concentration of methotrexate in some patients increased. Patients taking high doses of methotrexate, for example, with cancer or psoriasis, are advised to temporarily discontinue treatment with pantoprazole.
Other interactions Pantoprazole undergoes intensive metabolism in the liver with the participation of the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by the action of the CYP2C19 isoenzyme; other metabolic pathways include oxidation by the CYP3A4 isoenzyme. In studies of drug interactions that are also metabolized by these pathways, such as carbamazepine, diazepam, glibenclamide, nifedipine, and oral contraceptives containing levonorgestrel and ethinyl estradiol, no clinically significant interactions were detected.
The results of a number of interaction studies showed that pantoprazole does not affect the metabolism of drugs, which occurs with the participation of the CYP1A2 isoenzyme (such as caffeine, theophylline), the CYP2C9 isoenzyme (such as piroxicam, diclofenac, naproxen), the CYP2D6 isoenzyme (such as metoprolol), isoenzyme CYP2E1 (such as ethanol), and does not affect the absorption of digoxin associated with P-glycoprotein. Inhibitors of CYP2C19 isoenzyme activity, such as fluvoxamine, can increase the systemic exposure of pantoprazole.
Dose reduction may be needed in patients receiving long-term treatment with high doses of pantoprazole or in patients with liver failure. Inducers of the activity of CYP2C19 and CYP3A4 isoenzymes, such as rifampicin and Hypericum perforatum (Hypericum perforatum), can reduce the concentration of IDI metabolized by these enzyme systems in blood plasma.
There was no drug interaction with simultaneous use with antacids. With the simultaneous use of pantoprazole with antibiotics (clarithromycin, metronidazole, amoxicillin), clinically significant drug interactions were absent.
Dosage:
The drug Nolpaza® is taken orally, before meals, without chewing or crushing, with a sufficient amount of liquid. GERD, including erosive-ulcerative reflux esophagitis and symptoms associated with GERD: heartburn, acidic regurgitation, pain when swallowing:
• mild: recommended dose - 1 tablet of Nolpaza® (20 mg) per day;
• moderate and severe: the recommended dose is 1-2 tablets of Nolpaza® 40 mg per day (40-80 mg / day).
Relief of symptoms usually occurs within 2-4 weeks.
The course of therapy is 4-8 weeks. For prevention, as well as supporting long-term therapy, 20 mg / day are taken (1 tablet of Nolpaza® 20 mg), if necessary, the dose is increased to 40-80 mg / day. It is possible to take the drug "on demand" in case of symptoms. Peptic ulcer of the stomach and duodenum, erosive gastritis (including those associated with the use of non-steroidal anti-inflammatory drugs) At 40-80 mg per day.
The course of treatment is 2 weeks with exacerbation of duodenal ulcer, if this time is not enough, then healing can usually be achieved within the next 2 weeks of therapy. The course of treatment is 4-8 weeks with exacerbation of gastric ulcer and erosive gastritis. Anti-relapse treatment of peptic ulcer of the stomach and duodenum - 20 mg / day. Eradication of Helicobacter pylori The following combinations are recommended:
1. Nolpaza® 40 mg 2 times a day + 1000 mg amoxicillin 2 times a day + 500 mg clarithromycin
2 times a day 2. Nolpaza® 40 mg 2 times a day + metronidazole 500 mg 2 times a day + clarithromycin 500 mg 2 times a day
3. The drug Nolpaza® 40 mg 2 times a day + amoxicillin 1000 mg 2 times a day + metronidazole 500 mg 2 times a day.
The course of treatment is 7-14 days. Zollinger-Ellison Syndrome For long-term therapy of Zollinger-Ellison syndrome and other pathological hypersecretory conditions, treatment should begin with a daily dose of 80 mg (2 tablets of Nolpaza® 40 mg each). Then, if necessary, the dose can be increased or decreased, depending on the acidity of the gastric juice. Doses above 80 mg per day should be divided and applied twice daily. A temporary increase in the dose of pantoprazole is possible above 160 mg, but it should not last longer than is required to achieve acidity control.
The duration of treatment for Zollinger-Ellison syndrome and other pathological hypersecretory conditions is not limited, and the timing of therapy can be determined depending on the clinical need. In patients with severe hepatic impairment, the daily dose of pantoprazole should not exceed 20 mg per day (1 tablet of Nolpaza® 20 mg). In this regard, the use of pantoprazole in a dosage of 40 mg in this group of patients is not recommended.
The activity of “liver” enzymes should be regularly monitored during treatment with pantoprazole, especially with prolonged use of the drug. In case of increased activity of "liver" enzymes, treatment should be discontinued. No dose adjustment is required in elderly patients and patients with renal failure.
Due to the lack of data on the use of the drug Nolpaza® as part of combination antimicrobial therapy for Helicobacter pylori in patients with impaired renal function, as well as in patients with moderate to severe liver failure, the drug should not be used.
Overdose:
There were no cases of overdose as a result of the use of the drug Nolpaza®. Doses of pantoprazole up to 240 mg were administered intravenously for 2 minutes and were well tolerated. In case of an overdose and only when clinical manifestations appear, symptomatic and supportive therapy is carried out. Hemodialysis is ineffective.
