Pantoprazole

Pharmacological properties

mechanism of action. 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 is transformed into an active form in an acidic environment in parietal cells, where it inhibits the enzyme h + -k + phase, that is, it blocks the final stage of hydrochloric acid production in the stomach. inhibition is dose-dependent; pantoprazole inhibits both basal and stimulated acid secretion. in most patients, symptoms disappear within 2 weeks. when pantoprazole is used, as in the case of other proton pump inhibitors (PPIs) and h2 receptor inhibitors, the acidity in the stomach decreases and thus gastrin secretion increases in proportion to the decrease in acidity. increased gastrin secretion is reversible. 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 / in the use of the drug is the same.

When pantoprazole is used, fasting gastrin levels increase. With short-term use of the drug, the level of gastrin in most cases does not exceed the upper limit of the norm. With prolonged treatment, the level of gastrin in most cases doubles. Its excessive increase, however, occurs only in isolated cases. As a result, in a small number of cases with long-term treatment, there is a slight or moderate increase in the number of enterochromaffin-like (ECL) cells in the stomach (like adenomatoid hyperplasia). However, according to current studies, the formation of cells - the precursors of neuroendocrine tumors (atypical hyperplasia) or neuroendocrine tumors of the stomach, detected in animal experiments, was not observed in humans.

Based on the results of animal studies, one cannot exclude the effect of prolonged (more than 1 year) treatment with pantoprazole on the endocrine parameters of the thyroid gland.

During treatment with antisecretory drugs, the level of gastrin in the blood plasma increases in response to a decrease in acid secretion. In addition, due to a decrease in the acidity of the stomach, the level of chromogranin A (CgA) rises. Elevated levels of CgA may influence the results of studies in the diagnosis of neuroendocrine tumors. Available published data suggest that treatment with proton pump inhibitors should be discontinued for a period of 5 days to 2 weeks before measuring CgA levels. This allows the CgA level to return to the range of normal values, which may be erroneously elevated after treatment with PPI.

Pharmacokinetics The pharmacokinetic properties do not change after a single or repeated administration. In the dose range of 10–80 mg, the pharmacokinetics of pantoprazole in plasma remains linear both with oral administration and with iv administration.

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 with CYP2C19 followed by sulfate conjugation; Other metabolic pathways include oxidation with CYP3A4.

Final t_½ is about 1 h, and the clearance is 0.1 l / h / kg. Several cases of delayed elimination have been noted. Due to the specific binding of pantoprazole to the proton pump of T parietal cells_½ does not correlate with a much longer 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 desmethyl pantoprazole conjugated to sulfate. T_½ the main metabolite (about 1.5 hours) is not much higher than T_½ pantoprazole.

Slow metabolizers. ≈3% of Europeans have low functional activity of the enzyme CYP2C19; they are called slow metabolizers. In the body of such individuals, the metabolism of pantoprazole is probably mainly catalyzed by the enzyme CYP3A4. After taking a single dose of 40 mg of pantoprazole, the average, limited by the plasma-time plasma pharmacokinetic curve, was about 6 times greater in slow metabolizers than in individuals with the functionally active CYP 2C19 enzyme (fast metabolizers). The average peak plasma concentration increased by approximately 60%. These results do not affect the dosage of pantoprazole.

Impaired renal function. There are no recommendations for reducing the dose when prescribing pantoprazole to patients with impaired renal function (including patients on dialysis). Like healthy people, T_½ pantoprazole is short. Only a small amount of pantoprazole is dialyzed. Although the main metabolite has a moderately long T_½ (2-3 hours), elimination is still fast, therefore, cumulation does not occur.

Impaired liver function. Although in patients with cirrhosis (Child-Pugh classes A and B), T_½ increases to 7–9 hours, and AUC increases 5–7 times, C_max in blood serum increases slightly - 1.5 times in comparison with healthy volunteers.

Elderly patients. A slight increase in AUC and C_max in older volunteers, compared with younger volunteers, it also has no clinical significance.

Children. After a single administration of pantoprazole at a dose of 0.8 or 1.6 mg / kg body weight for children aged 2-16 years, there was no significant relationship between pantoprazole clearance and the patients age or body weight. AUC and volume of distribution were consistent with data from studies involving adults.

Indications

Reflux esophagitis. duodenal ulcer. stomach ulcer. Zollinger-Ellison syndrome and other hypersecretory pathological conditions.

Application

The drug is used as directed by a doctor and under proper medical supervision.

In / in the use of the drug is recommended only in case of impossibility of oral administration. There is data on the duration of iv treatment up to 7 days. Therefore, as soon as oral administration of pantoprazole becomes possible, a transition from iv administration of Controloc to oral administration at a dose of 40 mg is carried out.

Reflux esophagitis, duodenal ulcer, stomach ulcer. The recommended dose is 40 mg of pantoprazole (1 bottle) per day i / v.

Treatment of Zollinger-Ellison syndrome and other hypersecretory pathological conditions. For long-term treatment of Zollinger-Ellison syndrome and other hypersecretory pathological conditions, the recommended initial dose of the drug Controloc is 80 mg / day. If necessary, the dose can be titrated, increasing or decreasing, depending on the indicators of acid secretion in the stomach. Doses in excess of 80 mg per day should be divided into 2 administrations. A temporary increase in the dose of pantoprazole 160 mg is possible, but the duration of use should be limited only by the period necessary for adequate control of acid secretion.

In the event that a rapid decrease in acidity is needed, for most patients an initial dose of 2 x 80 mg is sufficient to achieve the desired level (10 meq / h) within 1 hour.

Preparation for use. The powder is dissolved in 10 ml of 0.9% solution of sodium chloride added to the bottle. The solution can be administered directly or after mixing with 100 ml of 0.9% solution of sodium chloride or 5% solution of glucose in plastic or glass bottles.

After dilution, the chemical and physical stability of the drug is maintained for 12 hours at a temperature of 25 ° C. From a microbiological point of view, a diluted preparation must be used immediately.

Controls should not be prepared or mixed with solvents other than those indicated above.

In / in the introduction of the drug must be carried out for 2-15 minutes.

The bottle is intended for single use only. Residues of the preparation or preparation whose physicochemical properties have changed (in particular, the color has changed, the precipitate has appeared) must be disposed of in accordance with the requirements of local legislation.

The diluted solution should have a transparent yellowish color.

Liver failure. Patients with severely impaired liver function should not exceed a daily dose of 20 mg (½ bottle of the drug Controloc, powder 40 mg).

Renal failure. For patients with impaired renal function, dose adjustment is not required.

Elderly patients. No dose adjustment is required.

Contraindications

Hypersensitivity to the active substance, benzimidazole derivatives and other components of the drug.

Side effects

The occurrence of adverse reactions was noted in about 5% of patients. the most common adverse reaction is thrombophlebitis at the injection site. diarrhea and headache occurred in about 1% of patients.

Undesirable effects by frequency of occurrence are classified into the following categories: very often (≥1 / 10), often (≥1 / 100, 1/10), infrequently (≥1 / 1000, 1/100), rarely (≥1 / 10,000 and 1/1000), very rarely (1/10 000), unknown (frequency not determined by available data).

For all adverse reactions that were reported in the post-marketing period, it is impossible to determine the frequency, therefore, they indicating "frequency is unknown."

Within each category, the frequency of adverse reactions is indicated in decreasing order of severity.

On the part of the blood and lymphatic system: rarely - agranulocytosis; very rarely - leukopenia, thrombocytopenia, pancytopenia.

On the part of the immune system: very rarely - hypersensitivity reactions (including anaphylactic reactions, anaphylactic shock).

Metabolism and metabolic disorders: rarely - hyperlipidemia and increased levels of lipids (TG, cholesterol), changes in body weight; unknown - hyponatremia, hypomagnesemia (see SPECIAL INSTRUCTIONS), hypocalcemia¹hypokalemia.

Mental disorders: infrequently - sleep disorders; rarely - depression (including exacerbation); very rarely - disorientation (including exacerbation); unknown - hallucinations, confusion (especially in patients with a tendency to these disorders, as well as an exacerbation of these symptoms, if any).

From the nervous system: infrequently - headache, dizziness; rarely - taste disturbances; unknown - paresthesia.

From the side of the organ of vision: rarely - impaired / blurred vision.

From the digestive tract: often - polyps from the fundus glands (benign); infrequently - diarrhea, nausea, vomiting, bloating, constipation, dry mouth, abdominal pain, discomfort.

From the hepatobiliary system: infrequently - an increase in the level of liver enzymes (transaminases, gamma-glutamyl transpeptidases); rarely - increased bilirubin level; unknown - damage to hepatocytes, jaundice, hepatocellular insufficiency.

On the part of the skin and subcutaneous tissues: infrequently - skin rash, exanthema, itching; rarely - urticaria, angioedema; unknown - Stevens-Johnson syndrome, Lyell syndrome, erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see SPECIAL INSTRUCTIONS).

From the musculoskeletal system and connective tissue: infrequently - fractures of the thigh, wrist, spine (see SPECIAL INSTRUCTIONS); rarely - arthralgia, myalgia; unknown - muscle cramps².

From the kidneys and urinary system: unknown - interstitial nephritis (with possible development of renal failure).

From the reproductive system and mammary glands: rarely - gynecomastia.

General disorders: often - thrombophlebitis at the injection site; infrequently - asthenia, fatigue, malaise; rarely - fever, peripheral edema.

¹ Hypocalcemia simultaneously with hypomagnesemia.

² Muscle spasm as a result of electrolyte imbalance.

special instructions

Malignant neoplasms of the stomach. the symptomatic response to pantoprazole can mask the symptoms of gastric malignancies and delay their diagnosis. in the presence of alarming symptoms (for example, in the case of a significant decrease in body weight, periodic vomiting, dysphagia, vomiting with blood, anemia, melena), as well as if there is a suspicion or presence of a stomach ulcer, the presence of a malignant process should be excluded. if symptoms persist with adequate treatment, an additional examination is necessary.

Impaired liver function. In patients with severely impaired liver function, it is necessary to regularly monitor the level of liver enzymes. In case of an increase in the level of hepatic enzymes, drug treatment should be discontinued (see APPLICATION).

HIV protease inhibitors. The combined use of pantoprazole with HIV protease inhibitors (such as atazanavir), the absorption of which depends on the intragastric pH, is not recommended due to a significant decrease in their bioavailability (see INTERACTIONS).

Gastrointestinal infections caused by bacteria. Drug treatment may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter or C. difficile.

Sodium. The drug contains 1 mmol of sodium (23 mg) in a bottle, that is, in fact, is a “sodium-free” drug.

Hypomagnesemia. Cases of severe hypomagnesemia have been observed in patients receiving PPIs, such as pantoprazole, for at least 3 months and in most cases for 1 year. The following serious clinical manifestations of hypomagnesemia may occur and begin to develop imperceptibly: fatigue, tetany, delirium, cramps, dizziness, and ventricular arrhythmia. In the case of hypomagnesemia, in most cases, the patients condition improved after substitution corrective therapy with magnesium preparations and discontinuation of PPI.

Patients who require long-term therapy, or patients who take PPIs simultaneously with digoxin or drugs that can cause hypomagnesemia (such as diuretics), need to determine the level of magnesium before starting PPI treatment and periodically during treatment.

Bone fractures. Long-term treatment (more than 1 year) with high doses of PPI may slightly increase the risk of fracture of the hip, wrist and spine, mainly in the elderly or in the presence of other risk factors. Observational studies indicate 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 of developing 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 a lesion occurs, especially in areas exposed to sunlight, accompanied by arthralgia, the patient should immediately consult a doctor who will consider the need to discontinue the drug. 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 influence the results of studies in the diagnosis of neuroendocrine tumors. To avoid such an effect, the treatment with the drug Controloc should be temporarily discontinued at least 5 days before assessing the level of CgA (see Pharmacodynamics). If the levels of CgA and gastrin have not returned to the normal range after the initial measurement, repeated measurements should be made 14 days after the withdrawal of PPI treatment.

Use during pregnancy and lactation

Pregnancy. Available data on the use of the drug Control in pregnant women (about 300-1000 reports of pregnancy results) indicate the absence of fetal or feto / neonatal toxicity of the drug. In animal studies, reproductive toxicity was observed. As a precaution, the use of the drug Control in pregnant women should be avoided.

Lactation. Animal studies have shown the excretion of pantoprazole in breast milk. Insufficient data on pantoprazole excretion into breast milk, however, this has been reported. The risk to newborns / infants cannot be ruled out. The decision to stop breastfeeding or to terminate / abstain from treatment with Controloc should be made taking into account the benefits of breastfeeding for a child and the benefits of treatment with Controloc for a woman.

Fertility. Pantoprazole did not cause impaired fertility in animal studies.

Children. Kontrolok, powder for solution for injection, is not recommended for use in children (under the age of 18 years), since data on the safety and effectiveness of the drug for this age category are limited. Currently available data are described in the Pharmacokinetics section, but dosage recommendations cannot be provided.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Pantoprazole does not affect or has a very slight effect on the reaction rate when driving vehicles or other mechanisms. The possible development of adverse reactions, such as dizziness and visual impairment, must be taken into account (see ADVERSE EFFECTS). In such cases, you should not drive vehicles or work with other mechanisms.

Interactions

Medicines, the absorption of which depends on the pH. as a result of complete and prolonged inhibition of hydrochloric acid secretion, pantoprazole can affect the absorption of drugs for which the pH value of gastric juice is an important factor in their bioavailability (for example, some antifungal drugs, such as ketoconazole, itraconazole, posaconazole or other drugs, such as erlotinib).

HIV protease inhibitors. The combined use of pantoprazole with HIV protease inhibitors (such as atazanavir), the absorption of which depends on the intragastric pH, is not recommended due to a significant decrease in their bioavailability (see SPECIAL INSTRUCTIONS).

In the case where the combined use of HIV protease inhibitors with PPI cannot be avoided, careful clinical monitoring (e.g. viral load) is recommended. Do not exceed the daily dose of pantoprazole in 20 mg. It may be necessary to adjust the dose of HIV protease inhibitors.

Coumarin anticoagulants (fenprocoumone and warfarin). The combined use of pantoprazole with warfarin or fenprocoumone did not affect the pharmacokinetics of warfarin, fenprocoumone or the international normalized index (PIM). However, an increase in PIM and an increase in prothrombin time have been reported in patients who simultaneously used PPIs and warfarin or fenprocoumon. An increase in PIM and an increase in prothrombin time can lead to the development of pathological bleeding and even death.In the case of such combined use, it is necessary to monitor the PID and prothrombin time.

Methotrexate. The concomitant use of high doses of methotrexate (e.g. 300 mg) and PPI has been reported to increase blood methotrexate levels in some patients. Patients taking high doses of methotrexate, for example, patients with cancer or psoriasis, are advised to temporarily stop treatment with pantoprazole.

Other interactions. Pantoprazole is largely metabolized in the liver through the cytochrome P450 enzyme system. The main metabolic pathway is demethylation with CYP2C19 and other metabolic pathways, including oxidation with the CYP3A4 enzyme. Studies with drugs that are also metabolized via these pathways, such as carbamazepine, diazepam, glibenclamide, nifedipine and oral contraceptives containing levonorgestrel and ethinyl estradiol, have not revealed clinically significant interactions.

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 that are metabolized using CYP1A2 (such as caffeine, theophylline), CYP2C9 (e.g. piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), CYP2Е1 ( such as ethanol), does not affect p-glycoprotein, which ensures the absorption of digoxin.

There was no interaction with simultaneously prescribed antacids.

Studies have been conducted to study the interaction of pantoprazole with simultaneously prescribed certain antibiotics (clarithromycin, metronidazole, amoxicillin). No clinically significant interactions between these drugs have been identified.

Medicines that inhibit or induce CYP2C19. CYP2C19 inhibitors, such as fluvoxamine, may increase the systemic effects of pantoprazole. Consideration should be given to the need to reduce the dose of the drug for patients who receive long-term therapy with pantoprazole in high doses, and for patients with impaired liver function. Inducers of enzymes that affect CYP2C19 and CYP3A4, such as rifampicin and St. Johns wort (Nurerisum perforatum), can reduce the plasma concentrations of PPIs that are metabolized through these enzyme systems.

Overdose

Symptoms of an overdose are unknown.

Doses up to 240 mg given iv for 2 minutes were well tolerated. Since pantoprazole extensively binds to proteins, it does not apply to drugs that can be readily excreted 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.

Storage conditions

In the original packaging at a temperature not exceeding 25 ° C.

UA / (PPIF) / 1018/0045.