Nolpaza

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Nolpaza® (Nolpaza®)

Composition:

Active substance: pantoprazole;

1 vial contains pantoprazole 40 mg (as pantoprazole sodium sesquihydrate);

Excipients: mannite (E 421), sodium citrate, sodium hydroxide.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: white or almost white, lyophilized, homogeneous porous block.

Pharmacotherapeutic group. Drugs for the treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors.

ATC code A02B C02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Pantoprazole is a substituted benzimidazole that inhibits gastric acid secretion by specifically targeting the proton pump of parietal cells.

Pantoprazole is transformed into its active form in the acidic environment of parietal cells, where it inhibits the H⁺K⁺-ATPase enzyme, thereby blocking the final step of hydrophilic gastric acid secretion. The inhibition is dose-dependent and affects both basal and stimulated gastric juice secretion. In most patients, symptom relief is achieved within 2 weeks. Treatment with pantoprazole, as with other proton pump inhibitors and H₂-receptor antagonists, reduces gastric acidity and proportionally increases gastrin secretion. The increase in gastrin levels is reversible. Since pantoprazole binds to enzymes distant from cellular receptors, it suppresses acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin).

Under the influence of pantoprazole, fasting gastrin levels increase. With short-term use, levels typically remain within the upper normal range. During long-term treatment, gastrin levels double in most cases. However, marked elevations have been observed only in isolated cases. As a consequence, a slight to moderate increase in the number of specific enterochromaffin-like (ECL) cells in the stomach occurs in most cases during prolonged therapy (similar to adenomatoid hyperplasia).

During treatment with antisecretory drugs, serum gastrin levels rise in response to reduced acid secretion. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may interfere with diagnostic tests for neuroendocrine tumors. Published data indicate that proton pump inhibitor (PPI) therapy should be discontinued for a period of 5 days to 2 weeks before measuring CgA levels, to allow CgA levels to return to the normal range, as this parameter may remain elevated after PPI treatment.

Pharmacokinetics.

General pharmacokinetics

Pharmacokinetics do not differ after single or repeated administration. Within the dose range of 10–80 mg, the plasma kinetics of pantoprazole are linear, both after oral and intravenous administration.

Distribution

Plasma protein binding of pantoprazole is approximately 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 via CYP2C19, followed by sulfate conjugation; another metabolic pathway involves oxidation via CYP3A4.

Elimination

The terminal half-life is approximately 1 hour, and clearance is about 0.1 L/h/kg. There have been several cases where patients exhibited delayed elimination. Due to the specific binding of pantoprazole to proton pumps in parietal cells, the elimination half-life does not reflect the much longer duration of pharmacological effect (acid secretion inhibition).

Renal excretion is the main elimination pathway (about 80%) for pantoprazole metabolites; the remainder is excreted in feces. The primary metabolite in both plasma and urine is desmethylpantoprazole, which is conjugated with sulfate. The half-life of the main metabolite (approximately 1.5 hours) is not substantially longer than that of pantoprazole.

Characteristics in patients/special patient groups:

Approximately 3% of Europeans lack functional CYP2C19 enzyme and are classified as poor metabolizers. In these individuals, pantoprazole metabolism may be primarily catalyzed by CYP3A4. After a single 40 mg dose, the mean area under the plasma concentration-time curve (AUC) was approximately 6 times higher in poor metabolizers compared to patients with functional CYP2C19 (extensive metabolizers). The mean maximum plasma concentration increased by approximately 60%. These observations have no relevance for pantoprazole dosing.

Dose adjustment is not required for patients with renal impairment, including those on hemodialysis. As in healthy individuals, the elimination half-life of pantoprazole remains short. Only a very small amount of pantoprazole can be dialyzed. Although the half-life of the main metabolite is slightly prolonged (2–3 hours), it is rapidly eliminated and therefore does not accumulate.

Although in patients with hepatic cirrhosis (Child–Pugh classes A and B), the half-life of pantoprazole increases to 7–9 hours and the AUC correspondingly increases 5–7 times, 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 observed in elderly volunteers compared to younger individuals is not clinically significant.

After single intravenous doses of 0.8 or 1.6 mg/kg pantoprazole administered to children aged 2 to 16 years, no significant relationship was observed between pantoprazole clearance and patient age or body weight. AUC and volume of distribution were comparable to values obtained in adult studies.

Clinical characteristics.

Indications.

The medicinal product is intended for treatment of adults.

• Gastroesophageal reflux disease (reflux esophagitis).
• Duodenal ulcer.
• Gastric ulcer.
• Zollinger–Ellison syndrome and other hypersecretory pathological conditions.

Contraindications.

Hypersensitivity to the active substance, benzimidazole derivatives, or any component of the drug.

Interaction with other medicinal products and other types of interactions.

Effect of pantoprazole on absorption of other medicinal products. Due to complete and prolonged inhibition of hydrochloric acid secretion, pantoprazole may reduce the absorption of drugs whose bioavailability depends on gastric pH (e.g., certain antifungal agents such as ketoconazole, itraconazole, posaconazole, or other drugs such as erlotinib).

Antiretroviral drugs (atazanavir). Concomitant use of proton pump inhibitors with atazanavir and other antiretroviral drugs whose absorption depends on gastric pH may lead to a significant reduction in their bioavailability 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, careful 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, there have been reports of increased INR and prolonged prothrombin time in patients receiving concomitant PPIs and warfarin or phenprocoumon. Increased INR and prolonged prothrombin time may lead to pathological bleeding and even death. In case of such concomitant use, monitoring of INR and prothrombin time is required.

Methotrexate. There have been reports that concomitant use of high-dose methotrexate (e.g., 300 mg) and proton pump inhibitors increases methotrexate blood levels in some patients. Patients receiving high doses of methotrexate, such as those with cancer or psoriasis, should temporarily discontinue pantoprazole therapy.

Other interactions. Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19, with additional metabolism via other pathways, including oxidation by the CYP3A4 enzyme. Studies with medicinal products also metabolized via these pathways—such as carbamazepine, diazepam, glyburide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—did not reveal clinically significant interactions.

Interaction between pantoprazole and other drugs metabolized via the same enzyme system cannot be ruled out.

Results from numerous studies on potential interactions indicate that pantoprazole does not affect the metabolism of active substances metabolized via 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 associated with digoxin absorption.

No interaction has been observed with concurrently administered antacids.

Studies on the interaction of pantoprazole with certain concurrently administered antibiotics (clarithromycin, metronidazole, amoxicillin) have been conducted. No clinically significant interactions were observed between these drugs.

Medicinal products that inhibit or induce CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, may increase the systemic exposure to pantoprazole. Consideration should be given to reducing the dose in patients receiving long-term, high-dose pantoprazole therapy and in patients with impaired liver function. Enzyme inducers affecting CYP2C19 and CYP3A4, such as rifampicin and St. John's wort (Hypericum perforatum), may reduce plasma concentrations of PPIs metabolized via these enzyme systems.

Effect of the medicinal product on laboratory parameters. False-positive results in certain urine screening tests for tetrahydrocannabinol (THC) have been reported in patients taking pantoprazole. Alternative testing methods should be considered to confirm results.

Special precautions for use.

Gastric malignancies. Symptomatic response to pantoprazole may mask symptoms of gastric malignancies and delay their diagnosis. In the presence of alarm symptoms (e.g., significant unintentional weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena), as well as in suspected or confirmed gastric ulcer, malignancy must be excluded.

If symptoms persist despite adequate therapy, further investigations are required.

Alarm symptoms. In the presence of alarm symptoms (e.g., significant unintentional weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena), as well as in suspected or confirmed gastric ulcer, malignancy must be excluded, because pantoprazole treatment may mask symptoms and delay diagnosis. If symptoms persist despite adequate therapy, further investigations are required.

Hepatic impairment. Patients with severe hepatic impairment require regular monitoring of liver enzymes. If liver enzymes increase, treatment with the drug should be discontinued (see section "Dosage and administration").

HIV protease inhibitors. Concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir), whose absorption is pH-dependent, is not recommended due to a significant reduction in their bioavailability (see section "Interaction with other medicinal products and other forms of interaction").

Gastrointestinal infections caused by bacteria. Pantoprazole, like other proton pump inhibitors (PPIs), 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, Campylobacter, or C. difficile.

Sodium. The drug contains less than 1 mmol of sodium (23 mg) per vial, i.e., is essentially sodium-free.

Hypomagnesemia. Rare cases of severe hypomagnesemia have been reported in patients treated with PPIs, including pantoprazole, for at least 3 months, and in most cases, for over a year. The following serious clinical manifestations of hypomagnesemia may occur and develop insidiously: fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia (see section "Special precautions for use"). In cases of hypomagnesemia (and hypocalcemia and/or hypokalemia associated with hypomagnesemia), the condition of patients improved in most cases after magnesium replacement therapy and discontinuation of PPI treatment.

Patients requiring long-term therapy, or those receiving PPIs concomitantly with digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), should have serum magnesium levels measured before starting PPI treatment and periodically during treatment.

Bone fractures. Long-term (more than 1 year) high-dose treatment with proton pump inhibitors may slightly increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other risk factors. Study results indicate that PPI use may increase the overall fracture risk by 10–40%. Some of these fractures may be attributable to other risk factors. Patients at risk of osteoporosis should receive treatment according to current clinical guidelines and should consume adequate amounts of vitamin D and calcium.

Severe cutaneous adverse reactions (SCARs). Severe cutaneous adverse reactions have been reported during pantoprazole use, including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal. The frequency of these reactions is unknown (see section "Adverse reactions").

When prescribing pantoprazole, patients should be informed about the signs and symptoms and closely monitored for skin reactions. If symptoms suggestive of these severe skin reactions occur, pantoprazole should be discontinued immediately, and alternative treatment options should be considered.

Subacute cutaneous lupus erythematosus. The use of proton pump inhibitors has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions develop, particularly in sun-exposed areas, and are accompanied by arthralgia, the patient should seek immediate medical attention, and discontinuation of Nольпаза® should be considered. Previous development of subacute cutaneous lupus erythematosus during treatment with proton pump inhibitors may increase the risk of recurrence when other PPIs are used.

Effect on laboratory test results.

Elevated chromogranin A (CgA) levels may interfere with diagnostic tests for neuroendocrine tumors. To avoid such interference, treatment with Nольпаза® should be temporarily discontinued at least 5 days before CgA assessment (see section "Pharmacodynamics"). If CgA and gastrin levels do not return to normal after initial measurement, repeat measurements should be performed 14 days after discontinuation of proton pump inhibitor therapy.

Use during pregnancy or breastfeeding.

Pregnancy. Available data on the use of Nольпаза® in pregnant women (approximately 300–1000 pregnancy outcome reports) indicate no embryonal or fetal/neonatal toxicity of the drug. Reproductive toxicity was observed in animal studies. As a precautionary measure, use of Nольпаза® in pregnant women should be avoided.

Breastfeeding. Animal studies have shown excretion of pantoprazole in breast milk. Data are available on the excretion of pantoprazole in human breast milk. The decision to discontinue/continue breastfeeding or to discontinue/continue treatment with Nольпаза® should be made considering the benefits of breastfeeding for the child and the benefits of treatment with Nольпаза® for the woman.

Fertility. Pantoprazole did not impair fertility in animal studies.

Ability to influence reaction speed when driving or operating machinery. Pantoprazole has no effect or only a negligible effect on reaction speed when driving or operating machinery. However, the possible occurrence of adverse reactions such as dizziness and visual disturbances should be taken into account. In such cases, driving or operating machinery should be avoided.

Method of Administration and Dosage

The drug should be administered to adults as prescribed and under direct medical supervision.

Intravenous administration of the drug is recommended only when oral administration is not possible. Data are available on intravenous treatment duration of up to 7 days. Therefore, whenever clinically feasible, a switch from intravenous administration of Nolpaza® to oral administration should be performed.

Gastroesophageal reflux disease, duodenal ulcer, gastric ulcer.

The recommended dose is 40 mg of pantoprazole (1 vial) once daily intravenously.

Treatment of Zollinger–Ellison syndrome and other hypersecretory conditions.

For long-term treatment of Zollinger–Ellison syndrome and other hypersecretory conditions, the recommended initial dose of Nolpaza® is 80 mg per day. If necessary, the dose may be titrated up or down depending on gastric acid secretion parameters. Doses exceeding 80 mg per day should be divided into two administrations. Temporary dose increases of pantoprazole to more than 160 mg may be possible, but the duration of use should be limited only to the period required for adequate control of acid secretion.

If rapid reduction of acidity is required, an initial dose of 2 × 80 mg is sufficient for most patients to achieve the desired level (< 10 mEq/h) within 1 hour.

Preparation for use.

The powder should be dissolved in 10 mL of 0.9% sodium chloride solution provided in the vial. The solution may be administered directly or after dilution with 100 mL of 0.9% sodium chloride solution or 5% glucose solution in plastic or glass bottles.

After reconstitution, the chemical and physical stability of the drug is maintained for 12 hours at 25 °C. From a microbiological standpoint, the diluted solution should be used immediately.

Nolpaza® must not be prepared or mixed with other solvents except those specified above.

Intravenous administration of the drug should be performed over 2–15 minutes.

The vial is intended for single use only. Before administration, the drug in the vial should be visually inspected (particularly for color change and presence of precipitate).

The reconstituted solution should be clear and yellowish.

Hepatic impairment. In patients with severe hepatic impairment, the daily dose should not exceed 20 mg (½ vial of Nolpaza®, lyophilisate for injection solution, 40 mg) (see section "Special precautions").

Renal impairment. Patients with renal impairment do not require dose adjustment.

Elderly patients do not require dose adjustment.

Children.

Nolpaza®, lyophilisate for injection solution, 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. Available data are described in the section "Pharmacokinetics"; however, dosage recommendations cannot be provided.

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 easily removed by dialysis.

In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy should be administered. There are no recommendations for specific antidotal therapy.

Adverse reactions

Adverse reactions may be expected in approximately 5% of patients. The most common adverse reaction is thrombophlebitis at the site of administration.

Undesirable effects are classified by frequency of occurrence as follows: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), and not known (frequency cannot be estimated from available data).

Blood and lymphatic system disorders

Rare: agranulocytosis.

Very rare: leukopenia, thrombocytopenia, pancytopenia.

Immune system disorders

Rare: hypersensitivity reactions (including anaphylactic reactions, anaphylactic shock).

Metabolism and nutrition disorders

Rare: hyperlipidemia and increased lipid levels (triglycerides, cholesterol), changes in body weight.

Not known: hyponatremia, hypomagnesemia (see section "Special precautions"), hypocalcemia¹, hypokalemia¹.

Psychiatric disorders

Uncommon: sleep disorders.

Rare: depression (including exacerbation).

Very rare: disorientation (including exacerbation).

Not known: hallucinations, confusion (particularly in patients predisposed to such disorders, as well as exacerbation of these symptoms if present in medical history).

Nervous system disorders

Uncommon: headache, dizziness.

Rare: taste disturbances.

Not known: paraesthesia.

Eye disorders

Rare: visual disturbances/blurred vision.

Gastrointestinal disorders

Common: fundic gland polyps.

Uncommon: diarrhea, nausea, vomiting, bloating, constipation, dry mouth, abdominal pain and discomfort.

Not known: microscopic colitis.

Hepatobiliary disorders

Uncommon: increased levels of liver enzymes (transaminases, γ-GT).

Rare: increased bilirubin levels.

Not known: hepatocellular injury, jaundice, hepatocellular failure.

Skin and subcutaneous tissue disorders

Uncommon: skin rashes, exanthema, pruritus.

Rare: urticaria, angioneurotic edema.

Not known: Stevens-Johnson syndrome, Lyell's syndrome, erythema multiforme, toxic epidermal necrolysis (TEN), photosensitivity, subacute cutaneous lupus erythematosus (see section "Special precautions"), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders

Uncommon: fractures of the femur, wrist, spine (see section "Special precautions").

Rare: arthralgia, myalgia.

Not known: muscle spasms².

Renal and urinary disorders

Not known: tubulointerstitial nephritis (TIN) (with possible development of renal failure).

Reproductive system and breast disorders

Rare: gynecomastia.

General disorders

Common: thrombophlebitis at the site of administration.

Uncommon: asthenia, fatigue, malaise.

Rare: increased body temperature, peripheral edema.

¹ Hypocalcemia and/or hypokalemia may be associated with the occurrence of hypomagnesemia (see section "Special precautions").

² Muscle spasms as a consequence of electrolyte imbalance.

Reporting of suspected adverse reactions

Reporting of adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance System at the following link: https://aisf.dec.gov.ua.

Shelf life. 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 stability for use is maintained for 12 hours at 25 °C.

From a microbiological standpoint, the product should be used immediately.

If the product is not used immediately, the person administering the product is responsible for the storage period and conditions prior to use.

Packaging.

Lyophilisate in 15 ml vials; packs of 1, 5, 10 or 20 vials in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's name and address.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.