Instructions for Nolpaza lyophilized for preparation of solution for injection 40 mg vial No. 1
Composition
active ingredient: pantoprazole;
1 bottle contains 40 mg of pantoprazole (as pantoprazole sodium sesquihydrate);
excipients: mannitol (E 421), sodium citrate, sodium hydroxide.
Dosage form
Lyophilisate for solution for injection.
Main physicochemical properties: white or almost white, lyophilized, homogeneous porous briquette.
Pharmacotherapeutic group
Drugs for the treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors.
ATX code A02B C02.
Pharmacological properties
Pharmacodynamics
Mechanism of action
Pantoprazole is a substituted benzimidazole that blocks the secretion of hydrochloric acid in the stomach through a specific effect on the proton pump of parietal cells.
Pantoprazole is transformed into the active form in the acidic environment of parietal cells, where it blocks the enzyme H+K+-ATPase, namely the final stage of hydrophilic secretion of hydrochloric acid in the stomach. Inhibition is dose-dependent and affects basal and stimulated secretion of gastric juice. In most patients, a reduction in symptoms is achieved within 2 weeks. Treatment with pantoprazole, as with other proton pump inhibitors and H2-receptor inhibitors, reduces the level of gastric acidity and proportionally increases gastrin secretion. The increase in gastrin is reversible. Since pantoprazole binds to enzymes that are distant from cell receptors, it affects the secretion of hydrochloric acid regardless of stimulation by other substances (acetylcholine, histamine, gastrin).
Pantoprazole increases fasting gastrin levels. In short-term use, in most cases they do not exceed the upper limit of normal. In long-term treatment, gastrin levels double in most cases. However, excessive increases have only been observed in isolated cases. As a result, there is a slight to moderate increase in the number of specific endocrine cells (ECL) in the stomach in most cases during long-term treatment (similar to adenomatoid hyperplasia).
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. Published evidence suggests that proton pump inhibitor treatment should be discontinued for 5 days to 2 weeks prior to CgA measurements to allow CgA levels to return to the normal range, as CgA levels may be elevated following treatment with proton pump inhibitors (PPIs).
Pharmacokinetics
General pharmacokinetics
The pharmacokinetics do not differ after single or repeated administration. In the dose range of 10–80 mg, the plasma kinetics of pantoprazole are linear after both oral and intravenous administration.
Distribution
The plasma protein binding of pantoprazole is approximately 98%. The volume of distribution is approximately 0.15 l/kg.
Breeding
The substance is almost exclusively metabolised in the liver. The main metabolic pathway is demethylation by CYP2C19 followed by sulphate conjugation, while other metabolic pathways include oxidation by CYP3A4. The terminal half-life is approximately 1 hour and the clearance is approximately 0.1 l/h/kg. There have been a few cases where patients have experienced delayed elimination. Due to the specific binding of pantoprazole to the proton pumps of the parietal cells, the half-life does not correspond to the much longer duration of action (inhibition of acid secretion).
Renal excretion is the main route of elimination (about 80%) for the metabolites of pantoprazole, the remainder being excreted in the faeces. The main metabolite in both plasma and urine is desmethylpantoprazole, which is conjugated with sulphate. The half-life of the main metabolite (about 1.5 hours) is not much longer than that of pantoprazole.
Characteristics in patients/special patient groups:
Approximately 3% of Europeans lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals, the metabolism of pantoprazole is probably catalysed primarily by CYP3A4. After a single dose of 40 mg pantoprazole, the mean area under the pharmacokinetic concentration-time curve (AUC) was approximately 6-fold higher in poor metabolisers than in patients with a functional CYP2C19 enzyme (extensive metabolisers). The mean maximum plasma concentration was increased by approximately 60%. These observations are not relevant to the dosage of pantoprazole.
Although in patients with liver cirrhosis (Child-Pugh classes A and B) the half-life increases to 7-9 hours and the AUC value increases 5-7-fold, the maximum plasma concentration of pantoprazole increases only 1.5-fold compared to healthy volunteers.
The slight increase in AUC and maximum plasma concentration of pantoprazole in elderly volunteers compared to young volunteers is also not clinically significant.
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. Gastric ulcer. Zollinger-Ellison syndrome and other hypersecretory pathological conditions.
Contraindication
Hypersensitivity to the active substance, benzimidazole derivatives and any component of the drug.
Interaction with other medicinal products and other types of interactions
Effect of pantoprazole on the absorption of other drugs: Due to the complete and long-term inhibition of hydrochloric acid secretion, pantoprazole may reduce the absorption of drugs whose bioavailability depends on the pH of the gastric juice (e.g. some antifungal drugs such as ketoconazole, itraconazole, posaconazole, or other drugs such as erlotinib).
Anti-HIV drugs (atazanavir). Concomitant use of proton pump inhibitors with atazanavir and other anti-HIV drugs whose absorption depends on gastric pH may significantly reduce the bioavailability of the latter and affect their efficacy. Therefore, concomitant use of proton pump inhibitors with atazanavir is not recommended.
If concomitant use of HIV protease inhibitors with proton pump inhibitors 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 INR (international normalized ratio). 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 such concomitant use, INR and prothrombin time should be monitored.
Methotrexate: Concomitant use of high doses of methotrexate (e.g. 300 mg) and proton pump inhibitors has been reported to increase blood levels of methotrexate in some patients. Patients receiving high doses of methotrexate, e.g. for 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 of the interaction of pantoprazole with certain antibiotics (clarithromycin, metronidazole, amoxicillin) administered concomitantly have been conducted. 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. 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 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.
Alarming symptoms present. In the presence of alarming symptoms (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia, melena) and in the presence or suspicion of gastric ulcer, malignancy should be excluded, as treatment with pantoprazole may mask symptoms and delay diagnosis. If symptoms persist despite adequate treatment, further investigation 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. Pantoprazole, like other proton pump inhibitors, may increase the number of bacteria normally present in the upper gastrointestinal tract. Treatment with the drug 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, i.e. essentially sodium-free.
Hypomagnesemia: Severe hypomagnesemia has been reported in patients receiving PPIs such as pantoprazole for at least three months, and in most cases for a year. 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 proton pump inhibitors may slightly increase the risk of hip, wrist and spine fractures, mainly in elderly patients or in the presence of other risk factors. The results of the study indicate that the use of proton pump inhibitors 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 proton pump inhibitors has been associated with very rare cases of subacute cutaneous lupus erythematosus. If lesions occur, especially in areas exposed to sunlight, and this is accompanied by arthralgia, the patient should immediately consult a doctor who will consider the need to discontinue the use of Nolpaza®. The occurrence of subacute cutaneous lupus erythematosus in patients during previous therapy with proton pump inhibitors may increase the risk of its development with the use of other proton pump inhibitors.
Impact on laboratory test results.
Elevated levels of chromogranin A (CgA) may interfere with the results of tests for the diagnosis of neuroendocrine tumors. To avoid this interference, treatment with Nolpaza® should be temporarily discontinued for at least 5 days before CgA measurements (see section 5.2). 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 proton pump inhibitor treatment.
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 adverse reactions, such as dizziness and visual disturbances. In such cases, one should not drive or use machines.
Use during pregnancy or breastfeeding
Pregnancy. Experience with the drug in pregnant women is limited. Reproductive toxicity was observed in animal reproduction studies. The potential risk to humans is unknown. Nolpaza® should not be used during pregnancy unless clearly necessary.
Breastfeeding. Animal studies have shown excretion of pantoprazole in breast milk. There are data on the excretion of pantoprazole in human breast milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Nolpaza® therapy taking into account the benefit of breast-feeding for the child and the benefit of Nolpaza® therapy for the woman.
Fertility: Pantoprazole did not impair fertility in animal studies.
Method of administration and doses
The drug is used by adults as prescribed and under the direct supervision of a physician.
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, if clinically feasible, a transition from intravenous administration of Nolpaza to oral administration is carried out.
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 Nolpaza 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.
Nolpaza cannot be prepared or mixed with solvents other than those mentioned above.
Intravenous administration of the drug should be carried out over 2–15 minutes.
The vial is for single use only. Before use, the product in the vial should be visually inspected (in particular, for discoloration, presence of sediment).
The diluted solution should have a clear yellowish color.
Hepatic insufficiency. Patients with severe liver dysfunction should not exceed a daily dose of 20 mg (½ vial of Nolpaza, lyophilisate for solution for injection, 40 mg each) (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
Nolpaza®, lyophilisate for solution for injection, 40 mg, is not recommended for use in children (under 18 years of age) as data on safety and efficacy in this age group are limited. The 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 can be expected to 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 by 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), unknown (frequency not determined based on available data).
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.
Not known: hyponatremia, hypomagnesemia (see section "Special warnings and precautions for use"), hypocalcemia1, hypokalemia.
Mental disorders.
Uncommon: sleep disorders.
Rare: depression (including exacerbation).
Not known: hallucinations, confusion (especially in patients with a predisposition to these disorders, as well as exacerbation of these symptoms if they are present in the anamnesis).
From the nervous system.
Uncommon: headache, dizziness.
Rare: taste disorders.
Not known: paraesthesia.
From the organs of vision.
Rare: visual disturbances/blurred vision.
From the digestive tract.
Uncommon: diarrhoea, nausea, vomiting, abdominal bloating, constipation, dry mouth, abdominal pain and discomfort.
On the part of the hepatobiliary system.
Uncommon: increased liver enzymes (transaminases, g-GT).
Rare: increased bilirubin levels.
Not known: hepatocyte damage, jaundice, hepatocellular failure.
On the skin and subcutaneous tissue.
Uncommon: skin rash, exanthema, pruritus.
Rare: urticaria, angioedema.
Not known: Stevens-Johnson syndrome, Lyell's 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.
Not known: muscle spasm2.
On the part of the kidneys and urinary system.
Not known: 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
3 years.
Storage conditions
Store in the original packaging to protect from light at a temperature not exceeding 25 °C.
Keep out of reach of children.
After reconstitution or reconstitution and dilution, chemical and physical in-use stability has been demonstrated for 12 hours at 25 ºC.
From a microbiological point of view, the product should be used immediately.
If the product is not used immediately, in-use storage times and conditions are the responsibility of the user.
Packaging
Lyophilisate in 15 ml vials; 1 vial in a cardboard box.
Vacation category
According to the recipe.
Producer
KRKA, dd, Novo mesto, Slovenia.
Location of the manufacturer and its business address
Smarjeska cesta 6, 8501 Novo mesto. Slovenia/Smarjeska cesta 6, 8501 Novo mesto, Slovenia.
