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 gastric acid production. Inhibition is dose-dependent, pantoprazole inhibits both basal and stimulated acid secretion. In most patients, symptoms resolve within 2 weeks. When pantoprazole is used, as with other proton pump inhibitors (PPIs) and H2-receptor inhibitors, gastric acidity decreases and gastrin secretion increases 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 the secretion of hydrochloric acid regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same with oral and intravenous administration of the drug.
When using pantoprazole, the level of gastrin increases 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, the level of gastrin in most cases increases by half. Its excessive increase, however, occurs only in isolated cases. As a result, in a small number of cases with long-term treatment, a slight or moderate increase in the number of enterochromaffin-like (ECL) cells in the stomach (similar to adenomatoid hyperplasia) is noted. However, according to studies conducted to date, the formation of cells - precursors of neuroendocrine tumors (atypical hyperplasia) or neuroendocrine tumors of the stomach, identified in animal experiments, has not been observed in humans.
Based on the results of animal studies, the effect of long-term (more than 1 year) treatment with pantoprazole on endocrine parameters of the thyroid gland cannot be excluded.
During treatment with antisecretory drugs, plasma 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 for 5 days to 2 weeks before CgA measurements. This allows CgA levels to return to the normal range, which may be falsely elevated after PPI treatment.
Pharmacokinetics. Pharmacokinetic properties do not change after single or repeated administration. In the dose range of 10-80 mg, the pharmacokinetics of pantoprazole in plasma remains linear both after oral administration and intravenous 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 by CYP2C19 followed by sulfate conjugation; other metabolic pathways include oxidation by CYP3A4.
Elimination. The terminal T½ is about 1 h and the clearance is 0.1 l/h/kg. Several cases of delayed elimination have been reported. Due to the specific binding of pantoprazole to the proton pump of the parietal cells, the T½ does not correlate with the much longer duration of action (inhibition of acid secretion).
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. T ½ of the main metabolite (about 1.5 hours) is not much higher than T ½ of pantoprazole.
Special patient groups. Poor metabolisers. ≈3% of Europeans have a low functional activity 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, pharmacokinetically limited plasma concentration-time curve was approximately 6-fold higher in poor metabolisers than in subjects with a functionally active CYP 2C19 enzyme (extensive metabolisers). The mean peak plasma concentration was increased by approximately 60%. These findings do not influence the posology of pantoprazole.
Renal impairment. There are no recommendations for dose reduction when prescribing pantoprazole to patients with renal impairment (including patients on dialysis). As in healthy subjects, the T½ of pantoprazole is short. Only a small amount of pantoprazole is dialyzed. Despite the fact that the main metabolite has a moderately long T½ (2-3 h), elimination is still rapid, so cumulation does not occur.
Hepatic impairment. Although in patients with cirrhosis of the liver (Child-Pugh classes A and B) T½ increases to 7-9 hours and AUC increases 5-7 times, Cmax in serum increases slightly - 1.5 times compared to healthy volunteers.
Children: After single administration of pantoprazole at a dose of 0.8 or 1.6 mg/kg body weight to children aged 2-16 years, there was no significant relationship between the clearance of pantoprazole and the age or body weight of the patient. The AUC and volume of distribution were consistent with those obtained in studies involving adults.
Indication
Reflux esophagitis. duodenal ulcer. gastric ulcer. Zollinger-Ellison syndrome and other hypersecretory pathological conditions.
Application
The drug is used as prescribed by a doctor and under proper medical supervision.
Intravenous administration of the drug is recommended only if oral administration is not possible. There is evidence of the duration of intravenous treatment up to 7 days. Therefore, as soon as oral administration of pantoprazole becomes possible, a transition from intravenous administration of Controloc to oral administration at a dose of 40 mg is made.
Reflux esophagitis, duodenal ulcer, gastric ulcer. The recommended dose is 40 mg pantoprazole (1 vial) per day intravenously.
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 Controloc is 80 mg/day. If necessary, the dose can be titrated up or down, depending on the indicators of acid secretion in the stomach. Doses exceeding 80 mg per day should be divided into 2 administrations. A temporary increase in the dose of pantoprazole to 160 mg is possible, but the duration of use should be limited only to the period necessary for adequate control of acid secretion.
If rapid reduction of acidity is required, an initial dose of 2 x 80 mg is sufficient for most patients to achieve the desired level (10 mEq/h) within 1 hour.
Preparation for use. The powder is dissolved in 10 ml of 0.9% sodium chloride solution, which is added to the vial. The solution can be administered directly or after mixing with 100 ml of 0.9% sodium chloride solution or 5% glucose solution in plastic or glass vials.
After dilution, chemical and physical in-use stability has been demonstrated for 12 hours at 25°C. From a microbiological point of view, the diluted product should be used immediately.
Controloc should not be prepared or mixed with solvents other than those specified above.
Intravenous administration of the drug should be carried out within 2-15 minutes.
The vial is for single use only. Any unused product or any product that has changed its physical and chemical properties (e.g., color, precipitate) should be disposed of in accordance with local regulations.
The diluted solution should have a clear yellowish color.
Hepatic impairment: Patients with severe hepatic impairment should not exceed a daily dose of 20 mg (½ vial of Controloc, 40 mg powder).
Renal impairment: No dose adjustment is required for patients with renal impairment.
Elderly patients: No dose adjustment is required.
Contraindication
Hypersensitivity to the active substance, benzimidazole derivatives and other components of the drug.
Side effects
Adverse reactions were observed in about 5% of patients. The most common adverse reaction was thrombophlebitis at the injection site. Diarrhea and headache occurred in about 1% of patients.
Adverse effects are classified by frequency of occurrence into the following categories: very common (≥1/10), common (≥1/100, 1/10), uncommon (≥1/1000, 1/100), rare (≥1/10,000 and 1/1000), very rare (1/10,000), unknown (frequency not determined based on available data).
For all adverse reactions reported in the post-marketing period, it is not possible to determine the frequency and are therefore indicated as “frequency unknown”.
Within each category, the frequency of adverse reactions is listed in order of decreasing seriousness.
From 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 lipid levels (TG, cholesterol), changes in body weight; unknown - hyponatremia, hypomagnesemia (see Features of use), hypocalcemia 1, hypokalemia.
Psychiatric disorders: infrequently - sleep disorders; rarely - depression (including exacerbation); very rarely - disorientation (including exacerbation); unknown - hallucinations, confusion (especially in patients with a predisposition to these disorders, as well as exacerbation of these symptoms if they are present).
From the nervous system: infrequently - headache, dizziness; rarely - taste disturbance; unknown - paresthesia.
On the part of the organ of vision: rarely - visual disturbances/blurring.
Gastrointestinal tract: often - fundic gland polyps (benign); infrequently - diarrhea, nausea, vomiting, bloating, constipation, dry mouth, abdominal pain, discomfort.
Skin and subcutaneous tissue disorders: infrequently - skin rash, rash, itching; rarely - urticaria, angioedema; unknown - Stevens-Johnson syndrome, Lyell's syndrome, erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see Precautions).
Musculoskeletal and connective tissue disorders: uncommon - fractures of the hip, wrist, spine (see Special warnings and precautions for use); rare - arthralgia, myalgia; unknown - muscle spasms 2.
Renal and urinary disorders: not known - 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. Symptomatic response to the use of pantoprazole may mask the symptoms of malignant neoplasms of the stomach and delay their diagnosis. In the presence of alarming symptoms (for example, in the case of significant weight loss, recurrent vomiting, dysphagia, haematemesis, anemia, melena), as well as in the case of suspicion or presence of a gastric ulcer, the presence of a malignant process should be excluded. If symptoms persist with adequate treatment, additional examination is necessary.
Hepatic impairment: In patients with severe hepatic impairment, liver enzymes should be monitored regularly. If liver enzymes increase, treatment should be discontinued (see Dosage & Administration).
HIV protease inhibitors: Concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir), whose absorption depends on intragastric pH, is not recommended due to a significant reduction in their bioavailability (see Interactions with other medicinal products).
Gastrointestinal infections caused by bacteria. Treatment with this medicine may slightly increase the risk of developing gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile.
Sodium: This medicine contains 1 mmol sodium (23 mg) per vial, meaning it is essentially “sodium-free”.
Hypomagnesemia: Severe hypomagnesemia has been reported 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 may initially be insidious: fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmias. In the case of hypomagnesemia, the condition of the patients improved in most cases 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.
Bone fractures. Long-term treatment (more than 1 year) with high doses of PPIs 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 the use of PPIs 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.
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, accompanied by joint pain, 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 the use of other PPIs.
Impact on laboratory test results.
Elevated chromogranin A (CgA) levels may interfere with the results of tests for the diagnosis of neuroendocrine tumors. To avoid this interference, treatment with Controloc should be temporarily discontinued for at least 5 days prior to the assessment of CgA levels (see Pharmacodynamics). If CgA and gastrin levels have not returned to the normal range after the initial measurement, repeat measurements should be performed 14 days after discontinuation of PPI treatment.
Use during pregnancy and breastfeeding
Breastfeeding. Animal studies have shown excretion of pantoprazole in breast milk. There is insufficient information on the excretion of pantoprazole in human milk, but it 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 Controloc therapy taking into account the benefit of breast-feeding for the child and the benefit of Controloc therapy for the woman.
Fertility: Pantoprazole did not cause impaired fertility in animal studies.
Children: Controloc, powder for solution for injection, is not recommended for use in children (under 18 years of age) as safety and efficacy data in this age group are limited. Currently available data are described in the Pharmacokinetics section, but no dosage recommendations can be made.
Ability to influence the reaction rate when driving vehicles or operating other mechanisms. Pantoprazole has no or very minor influence on the reaction rate when driving vehicles or operating other mechanisms. It is necessary to take into account the possible development of adverse reactions, such as dizziness and visual disturbances (see Side effects). In such cases, you should not drive vehicles or operate other mechanisms.
Interactions
Medicinal products whose absorption depends on pH: As a result of complete and prolonged inhibition of hydrochloric acid secretion, pantoprazole may affect the absorption of drugs for which the pH of the gastric juice is an important factor in their bioavailability (e.g. some antifungal drugs such as ketoconazole, itraconazole, posaconazole or other drugs such as erlotinib).
HIV protease inhibitors: Concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir), whose absorption depends on intragastric pH, is not recommended due to a significant reduction in their bioavailability (see Precautions).
In cases where the combined use of HIV protease inhibitors with PPIs can 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 death. In the case of such combined 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 blood levels of methotrexate in some patients. Patients taking high doses of methotrexate, e.g. for cancer or psoriasis, are advised to temporarily discontinue pantoprazole treatment.
Other interactions. Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19 and other metabolic pathways, including oxidation by CYP3A4. Studies with drugs also metabolized by these pathways, such as carbamazepine, diazepam, glibenclamide, nifedipine and oral contraceptives containing levonorgestrel and ethinylestradiol, have not revealed clinically significant interactions.
Interactions of pantoprazole with other drugs that are metabolized through the same 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 (such as caffeine, theophylline), CYP2C9 (such as piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), CYP2E1 (such as ethanol), and does not affect p-glycoprotein, which ensures the absorption of digoxin.
No interactions with concomitantly administered antacids were identified.
A study was conducted to study the interaction of pantoprazole with certain antibiotics (clarithromycin, metronidazole, amoxicillin) administered concomitantly. No clinically significant interactions between these drugs were identified.
Medicinal products that inhibit or induce CYP2C19. 2C19 inhibitors, such as fluvoxamine, may increase the systemic exposure of pantoprazole. Dose reduction should be considered in patients receiving long-term high-dose pantoprazole therapy and in patients with impaired hepatic 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 metabolized by these enzyme systems.
Overdose
Symptoms of overdose are unknown.
Doses up to 240 mg administered intravenously over 2 minutes were 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.
In the original packaging at a temperature not exceeding 25 °C.
UA / (PPIF) / 1018/0045.
