Instructions Proxium enteric-coated tablets 40 mg blister No. 32
Composition
active ingredient: pantoprazole;
1 vial contains 40 mg of pantoprazole (in the form of sodium sesquihydrate 46 mg);
excipient: disodium edetate.
Dosage form
Powder for solution for injection.
Main physicochemical properties: white or almost white powder.
Pharmacotherapeutic group
A drug for the treatment of acid-dependent diseases. Proton pump inhibitors. ATC 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 the 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 step in the production of gastric acid. The inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. Most patients are relieved of symptoms within 2 weeks. The use of pantoprazole, as with other proton pump inhibitors (PPIs) and H2-receptor inhibitors, reduces gastric acidity 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 cellular 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, gastrin levels do not exceed the upper limit of normal in most cases. In long-term treatment, gastrin levels double in most cases. However, excessive increases occur only in isolated cases. As a result, a small number of cases with long-term treatment have been observed with a mild to moderate increase in the number of enterochromaffin-like cells (ECL cells) in the stomach (similar to adenomatoid hyperplasia). However, according to studies conducted so far, the formation of precursor cells of neuroendocrine tumors (atypical hyperplasia) or neuroendocrine tumors of the stomach, which have been identified in animal experiments, 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 endocrine parameters of the thyroid gland cannot be 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 PPIs 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.
The pharmacokinetic properties do not change after single or repeated administration of the drug. In the dose range from 10 to 80 mg, the pharmacokinetics of pantoprazole in blood plasma remain linear both after oral and intravenous administration.
Distribution: The binding of pantoprazole to serum proteins is approximately 98%. The volume of distribution is approximately 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 half-life is approximately 1 hour 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 pumps of the parietal cells, the half-life 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 (approximately 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 (approximately 1.5 hours) is slightly longer than that of pantoprazole.
Special patient groups.
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 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 classes A and B) the half-life increases to 7-9 hours and the AUC increases 5-7-fold, the maximum serum concentration (Cmax) increases only slightly - 1.5-fold compared to that in healthy volunteers.
Elderly patients: The slight increase in AUC and Cmax in elderly volunteers compared to younger volunteers is also not clinically relevant.
Children: After 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 consistent with those obtained in studies in adults.
Indication
- Reflux esophagitis.
- Duodenal ulcer.
- Stomach ulcer.
- Zollinger-Ellison syndrome and other hypersecretory pathological conditions.
Contraindication
Hypersensitivity to the active substance, benzimidazole derivatives or to any component of the drug.
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, INR and prothrombin time should be monitored.
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. patients with cancer or psoriasis, are advised to temporarily discontinue pantoprazole treatment.
Other interactions. Pantoprazole is extensively metabolised in the liver via the cytochrome P450 enzyme system. The main route of metabolism is demethylation by CYP2C19 and other metabolic pathways, including oxidation by CYP3A4. Studies with medicinal products also metabolised by these pathways, such as carbamazepine, diazepam, glibenclamide, nifedipine and oral contraceptives containing levonorgestrel and ethinylestradiol, have not revealed any 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 (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 antibiotics (clarithromycin, metronidazole, amoxicillin) administered concomitantly. 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
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.
Hepatic impairment: Patients with severe hepatic impairment should have their liver enzymes monitored regularly. If liver enzymes increase, treatment with the drug should be discontinued (see section 4.2).
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 4.5).
Gastrointestinal infections caused by bacteria. Treatment with Proxium® may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or C. Difficile.
Sodium: This medicine contains less than 1 mmol sodium (23 mg) per vial, that is, essentially “sodium-free”.
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. 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 majority of 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.
Bone fractures: Long-term treatment (more than 1 year) with high doses of PPIs may modestly increase the risk of hip, wrist, and spine fractures, mainly in the elderly or in those with other risk factors.
Observational studies suggest that PPI use 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, and are accompanied by arthralgia, the patient should immediately consult a doctor who will consider discontinuing Proxium®. The occurrence of subacute cutaneous lupus erythematosus in patients on previous PPI therapy may increase the risk of its development with the use of other PPIs.
Impact on laboratory test results.
Elevated levels of CgA may interfere with the results of diagnostic tests for neuroendocrine tumors. To avoid this interference, treatment with Proxium® should be temporarily discontinued for at least 5 days prior to CgA measurement (see section 5.1). 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 therapy.
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, i.e. essentially 'sodium-free'.
Use during pregnancy or breastfeeding
Pregnancy. Available data on the use of Proxium® in pregnant women (approximately 300-1000 pregnancy outcomes) indicate no embryonal or foeto/neonatal toxicity of the drug. Reproductive toxicity has been observed in animal studies. As a precautionary measure, the use of Proxium® in pregnant women should be avoided.
Breastfeeding. Animal studies have shown excretion of pantoprazole in breast milk. There is insufficient data on the excretion of pantoprazole in human milk, but such excretion has been reported. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Proxium® therapy taking into account the benefit of breast-feeding for the child and the benefit of Proxium® 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
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 are data on 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 Proxium® to oral administration of pantoprazole at a dose of 40 mg is made.
Reflux esophagitis, duodenal ulcer, gastric ulcer.
The recommended dose is 40 mg of 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 Proxium® is 80 mg per 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 two administrations. A temporary increase in the dose of pantoprazole to more than 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.
Proxium® should not be prepared or mixed with solvents other than those specified above.
Intravenous administration of the drug should be carried out over 2–15 minutes.
The vial is for single use only. Any unused product or any product whose physicochemical properties have changed (e.g., color change, 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 Proxium®, 40 mg powder) (see section "Special warnings and precautions for use").
Renal impairment: Patients with impaired renal function do not require dose adjustment.
Elderly patients do not require dose adjustment.
Children
Proxium®, powder for solution for injection, is not recommended for use in children (under 18 years of age) as data on safety and efficacy in this age group are limited. Currently available data are described in the Pharmacokinetics section, but no dosage recommendations can be made.
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
Adverse reactions may occur in approximately 5% of patients. The most common adverse reaction is thrombophlebitis at the injection site. Diarrhea and headache occurred in approximately 1% of patients.
Adverse effects are classified according to the frequency of occurrence into the following categories:
very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10000 and < 1/1000), very rare (< 1/10000), frequency unknown (frequency cannot be estimated from the available data).
For all adverse reactions reported during the post-marketing period, it is not possible to determine the frequency and are therefore indicated as “frequency unknown”.
Within each frequency category, adverse reactions are presented in order of decreasing seriousness.
From the blood and lymphatic system.
Rare: agranulocytosis.
Very rare: leukopenia, thrombocytopenia, pancytopenia.
From the immune system.
Rare: hypersensitivity reactions (including anaphylactic reactions, anaphylactic shock).
Metabolism and metabolic disorders.
Rare: hyperlipidemia and increased lipid levels (triglycerides, cholesterol), changes in body weight.
Frequency not known: hyponatremia, hypomagnesemia (see section "Special warnings and precautions for use"), hypocalcemia1, hypokalemia.
Mental disorders.
Uncommon: sleep disorders.
Rare: depression (including exacerbation).
Frequency unknown: hallucinations, confusion (especially in patients with a predisposition to such disorders, as well as exacerbation of these symptoms in case of pre-existing conditions).
From the nervous system.
Uncommon: headache, dizziness.
Rare: taste disorders.
Frequency unknown: paresthesia.
From the organs of vision.
Rare: visual disturbances/blurred vision.
From the digestive tract.
Common: fundic gland polyps (benign).
Uncommon: diarrhoea, nausea, vomiting, abdominal bloating, constipation, dry mouth, abdominal pain and discomfort.
Frequency unknown: microscopic colitis.
On the part of the hepatobiliary system.
Uncommon: increased liver enzymes (transaminases, g-GT).
Rare: increased bilirubin levels.
Frequency unknown: hepatocyte damage, jaundice, hepatocellular failure.
On the skin and subcutaneous tissue.
Uncommon: skin rash, exanthema, pruritus.
Rare: urticaria, angioedema.
Frequency unknown: Stevens-Johnson syndrome, Lyell syndrome, erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special warnings and precautions for use").
On the part of the musculoskeletal system and connective tissue.
Uncommon: fractures of the hip, wrist, spine (see section "Special warnings and precautions for use").
Rare: arthralgia, myalgia.
Frequency not known: muscle spasm2.
On the part of the kidneys and urinary system.
Frequency unknown: interstitial nephritis (with possible development of renal failure).
From the reproductive system and mammary glands.
Rare: gynecomastia.
General disorders.
Common: thrombophlebitis at the injection site.
Uncommon: asthenia, fatigue, malaise.
Rare: fever, peripheral edema.
1 Hypocalcemia concomitant with hypomagnesemia.
2 Muscle spasm as a result of electrolyte imbalance.
Expiration date
2 years.
After dilution, the shelf life of the finished solution is 12 hours.
Storage conditions
Store in the original packaging at a temperature not exceeding 30 °C.
Keep out of reach of children.
Packaging
1 bottle in a cardboard box.
Vacation category
According to the recipe.
Producer
Laboratorios Normon S.A.
Location of the manufacturer and address of its place of business
Ronda de Valdecarriso, 6, Tres Cantos, 28760 Madrid, Spain.
