Nolpaza®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NOlPAZA® (NOLPAZA®)

Composition:

Active substance: pantoprazole;

one gastro-resistant tablet contains 40 mg of pantoprazole as pantoprazole sodium sesquihydrate;

Excipients : mannite (E 421), crospovidone (type A), crospovidone (type B), sodium carbonate, sorbitol (E 420), calcium stearate, hypromellose, povidone, titanium dioxide (E 171), yellow iron oxide (E 172), propylene glycol, methacrylic acid copolymer dispersion, sodium lauryl sulfate, polysorbate 80, talc, macrogol 6000.

Pharmaceutical form. Gastro-resistant tablets.

Main physicochemical characteristics: light yellowish-brown colored tablets, oval, slightly biconvex, coated with a film coating.

Pharmacotherapeutic group. Proton pump inhibitors. ATC code A02B C02.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action. Pantoprazole is a substituted benzimidazole that inhibits gastric hydrochloric acid secretion by specifically blocking the proton pumps of parietal cells.

Pantoprazole is transformed into its active form in the acidic environment of parietal cells, where it inhibits the enzyme H⁺-K⁺-ATPase, thereby blocking the final step of gastric acid production. Inhibition is dose-dependent and affects both basal and stimulated acid secretion. Most patients become symptom-free within 2 weeks. The use of pantoprazole, as with other proton pump inhibitors (PPIs) and H₂-receptor antagonists, reduces gastric acidity and consequently increases gastrin secretion proportionally to the reduction in acidity. Increased 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 following oral or intravenous administration.

With pantoprazole use, fasting gastrin levels increase. With short-term treatment, these levels usually do not exceed the upper limit of normal. With long-term treatment, gastrin levels typically double. Marked elevation occurs only in isolated cases. As a consequence, in a small number of cases during prolonged treatment, mild or moderate increase in gastric enterochromaffin-like (ECL) cells (similar to adenomatoid hyperplasia) may be observed. However, according to studies conducted to date, the formation of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors, which were observed in animal studies, has not been observed in humans.

Based on animal studies, an effect of long-term (more than one year) pantoprazole treatment on thyroid gland endocrine parameters cannot be excluded.

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. In addition, due to decreased gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may interfere with diagnostic testing for neuroendocrine tumors. Available published data indicate that treatment with proton pump inhibitors should be discontinued for a period of 5 days to 2 weeks before measuring CgA levels. This allows CgA levels to return to the normal range, which may otherwise be falsely elevated after PPI treatment.

Pharmacokinetics.

Absorption. Pantoprazole is rapidly absorbed, and maximum plasma concentrations are achieved after a single oral dose of 40 mg. On average, peak serum concentration of approximately 2–3 µg/mL is reached 2.5 hours after administration; plasma concentrations remain consistent after repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. Within the dose range of 10 to 80 mg, the pharmacokinetics of pantoprazole in plasma remain linear, both after oral administration and intravenous infusion. Absolute bioavailability of tablets is approximately 77%. Concomitant food intake does not affect AUC (area under the concentration-time curve) or peak serum concentration, and thus does not affect bioavailability. Food intake only increases the variability of the lag time.

Distribution. Plasma protein binding of pantoprazole is approximately 98%. Volume of distribution is about 0.15 L/kg.

Biological transformation. The substance is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation via CYP2C19, followed by sulfation; other metabolic pathways include oxidation via CYP3A4.

Elimination. The terminal half-life is approximately 1 hour, and clearance is 0.1 L/h/kg. A few cases of delayed elimination have been reported. Due to the specific binding of pantoprazole to proton pumps in parietal cells, the elimination half-life does not correlate with the much longer duration of action (acid secretion inhibition).

The majority of pantoprazole metabolites are excreted in urine (approximately 80%), the remainder in 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 only slightly longer than that of pantoprazole.

Special patient groups.

Slow metabolizers. Approximately 3% of Europeans have a functional deficiency in CYP2C19 enzyme activity; these individuals are referred to as slow metabolizers. In such individuals, pantoprazole metabolism is likely primarily catalyzed by CYP3A4. After a single 40 mg dose, the mean area under the plasma concentration-time curve was approximately 6 times higher in slow metabolizers compared to individuals with functionally active CYP2C19 (extensive metabolizers). The mean peak plasma concentration increased by approximately 60%. These findings do not affect pantoprazole dosing.

Renal impairment. No dosage adjustment recommendations are required when administering pantoprazole to patients with impaired renal function (including patients on dialysis). As in healthy individuals, the elimination half-life of pantoprazole remains short. Only very small amounts of pantoprazole are dialyzed. Although the main metabolite has a moderately prolonged half-life (2–3 hours), elimination remains rapid, so accumulation does not occur.

Hepatic impairment. Although in patients with liver cirrhosis (Child-Pugh classes A and B), the half-life increases to 7–9 hours and AUC increases 5–7 times, the peak serum concentration increases only slightly—by 1.5 times—compared to healthy volunteers.

Elderly patients. A slight increase in AUC and C_max in elderly volunteers compared to younger volunteers is not clinically significant.

Children. After a single oral dose of 20 or 40 mg pantoprazole, AUC and C_max in children aged 5 to 16 years were within the range of corresponding values in adults. After a single intravenous dose of pantoprazole at 0.8 or 1.6 mg/kg in children aged 2 to 16 years, no significant relationship was observed between pantoprazole clearance and age or body weight. AUC and volume of distribution corresponded to data obtained in adult studies.

Clinical characteristics.

Indications.

Adults and children aged 12 years and older.

• Gastroesophageal reflux disease (GERD).

Adults.

• Eradication of Helicobacter pylori (H. pylori) in patients with H. pylori-associated gastric and duodenal ulcers, in combination with appropriate antibiotics.
• Duodenal ulcer.
• Gastric ulcer.
• Zollinger-Ellison syndrome and other hypersecretory conditions.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Medicinal products whose absorption is pH-dependent. Due to complete and prolonged inhibition of gastric acid secretion, pantoprazole may affect the absorption of drugs for which gastric pH is an important factor in their bioavailability (e.g., certain antifungal agents 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 is pH-dependent, is not recommended due to a significant reduction in their bioavailability (see section "Special precautions for use").

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 administration 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. Elevated INR and prolonged prothrombin time may lead to clinically significant bleeding and even fatal outcomes. Monitoring of INR and prothrombin time is required when these drugs are used concomitantly.

Methotrexate. There have been reports of increased methotrexate blood levels in some patients when high-dose methotrexate (e.g., 300 mg) is administered concomitantly with proton pump inhibitors. Patients receiving high-dose methotrexate, such as those with cancer or psoriasis, should temporarily discontinue pantoprazole therapy.

Studies on other interactions
Pantoprazole is predominantly metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19, with additional metabolism via CYP3A4.

Studies with drugs that are also metabolized via these pathways—such as carbamazepine, diazepam, glyburide, nifedipine, phenprocoumon, and oral contraceptives containing levonorgestrel and ethinylestradiol—did not reveal clinically significant interactions.

Interactions between pantoprazole and other drugs metabolized via the same enzyme system cannot be excluded.

Results from studies on potential 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), or does not affect P-glycoprotein, which mediates digoxin absorption.

No interactions were observed with concomitantly administered antacids.

Specific interaction studies of pantoprazole with certain antibiotics (clarithromycin, metronidazole, amoxicillin) during co-administration have been conducted. No clinically significant interactions between these drugs were observed.

Medicinal products that inhibit or induce CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, may increase systemic exposure to pantoprazole. Consideration should be given to dose reduction 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.

Hepatic impairment. Patients with severe liver dysfunction should have regular monitoring of liver enzymes, especially during long-term treatment. If liver enzyme levels increase, treatment with the drug should be discontinued.

Combination therapy. During combination therapy, instructions for medical use of the corresponding medicinal products must be followed.

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 weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena), as well as in suspected or confirmed gastric ulcer, malignancy must be ruled out.

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

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 section "Interaction with other medicinal products and other forms of interaction").

Effect on vitamin B12 absorption

Pantoprazole may reduce absorption of vitamin B12 (cyanocobalamin) due to the development of hypo- or achlorhydria. This should be considered in patients with low body weight or risk factors for reduced vitamin B12 (cyanocobalamin) absorption, particularly during long-term treatment or in the presence of relevant clinical symptoms.

Long-term treatment. Patients undergoing long-term treatment, especially longer than 1 year, should be under regular medical supervision.

Gastrointestinal infections caused by bacteria

Treatment with the drug may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile.

Hypomagnesemia. Rare cases of severe hypomagnesemia have been reported in patients treated with PPIs, such as pantoprazole, for at least 3 months, and in most cases, after one year. The following serious clinical manifestations of hypomagnesemia may develop insidiously: fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. 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 replacement therapy with magnesium supplements and discontinuation of PPI treatment.

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

Bone fractures. Long-term treatment (more than 1 year) with high doses of proton pump inhibitors may moderately increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other risk factors. Observational studies suggest that the use of proton pump inhibitors may increase the overall risk of fractures by 10–40%. Some of these may be attributable to other risk factors. Patients at risk of developing 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 with the use of pantoprazole, including erythema multiforme, cases of Stevens–Johnson syndrome (SJS), 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 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 advice, and discontinuation of Nolpaza® should be considered. Development of subacute cutaneous lupus erythematosus in patients during prior therapy with proton pump inhibitors may increase the risk of its recurrence with other proton pump inhibitors.

Effect on laboratory test results.

Elevated chromogranin A (CgA) levels may interfere with diagnostic testing for neuroendocrine tumors. To avoid this interference, treatment with Nolpaza® should be temporarily discontinued at least 5 days before assessment of CgA levels (see section "Pharmacodynamics"). 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 proton pump inhibitor therapy.

Information about excipients

Nolpaza® contains sorbitol. Patients with rare hereditary fructose intolerance should not use this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy. Available data on the use of Nolpaza® in pregnant women indicate no embryonal or fetal/neonatal toxicity of the drug. Reproductive toxicity was observed in animal studies. As a precautionary measure, the use of Nolpaza® in pregnant women should be avoided.

Breastfeeding. Animal studies have shown excretion of pantoprazole into breast milk. There is insufficient data on excretion of pantoprazole into human breast milk, but such excretion has been reported. Risk to newborns/infants cannot be excluded. A decision to discontinue breastfeeding or to discontinue/abstain from Nolpaza® therapy should be made taking into account the benefit of breastfeeding for the child and the benefit of Nolpaza® therapy for the woman.

Fertility. Pantoprazole did not impair fertility in animal studies.

Ability to affect reaction speed when driving or operating machinery.

Pantoprazole has no effect or a negligible effect on reaction speed when driving or operating machinery. The possible occurrence of adverse reactions such as dizziness and visual disturbances should be taken into account (see section "Adverse reactions"). In such cases, patients should refrain from driving or operating machinery.

Method of Administration and Dosage

Nolpaza®, gastro-resistant tablets, should be taken whole, 1 hour before a meal, without chewing or crushing, with water.

Recommended Dosage

Adults and children aged 12 years and older

Treatment of reflux esophagitis.

The recommended dose is 1 tablet of Nolpaza® 40 mg once daily. In individual cases, the dose may be doubled (2 tablets of Nolpaza® 40 mg daily), especially if there is no response to treatment with other medications for reflux esophagitis. Treatment of reflux esophagitis usually requires 4 weeks. If this is insufficient, healing may be expected during the following 4 weeks.

Adults

Eradiсation of H. pylori in combination with two antibiotics.

In adult patients with gastric or duodenal ulcer and a positive H. pylori test result, eradication of the organism should be achieved using combination therapy. Local bacterial resistance data and national guidelines regarding the use and selection of appropriate antibacterial agents should be considered. Depending on susceptibility, the following therapeutic regimens may be prescribed for H. pylori eradication in adults:

a) 1 tablet of Nolpaza® 40 mg twice daily

• 1000 mg amoxicillin twice daily
• 500 mg clarithromycin twice daily;

b) 1 tablet of Nolpaza® 40 mg twice daily

• 400–500 mg metronidazole (or 500 mg tinidazole) twice daily
• 250–500 mg clarithromycin twice daily;

c) 1 tablet of Nolpaza® 40 mg twice daily

• 1000 mg amoxicillin twice daily
• 400–500 mg metronidazole (or 500 mg tinidazole) twice daily.

When using combination therapy for H. pylori eradication, the second tablet of Nolpaza® 40 mg should be taken in the evening, 1 hour before a meal. The treatment duration is 7 days and may be extended for another 7 days, with a total treatment duration not exceeding two weeks. If further treatment with pantoprazole is indicated to ensure ulcer healing, refer to the dosage recommendations for gastric and duodenal ulcers. If combination therapy is not indicated, e.g., in patients with a negative H. pylori test result, monotherapy with Nolpaza® 40 mg should be administered at the dosage specified below.

Treatment of gastric ulcer.

1 tablet of Nolpaza® 40 mg once daily. In individual cases, the dose may be doubled (2 tablets of Nolpaza® 40 mg daily), especially if there is no response to other medications.

Treatment of gastric ulcer usually requires 4 weeks. If this is insufficient, ulcer healing may be expected during the following 4 weeks.

Treatment of duodenal ulcer.

1 tablet of Nolpaza® 40 mg once daily. In individual cases, the dose may be doubled (2 tablets of Nolpaza® 40 mg daily), especially if there is no response to other medications.

Treatment of duodenal ulcer usually requires 2 weeks. If this is insufficient, ulcer healing may be expected during the following 2 weeks.

Treatment of Zollinger-Ellison syndrome and other hypersecretory conditions.

For long-term treatment of Zollinger-Ellison syndrome and other pathological hypersecretory conditions, the initial daily dose is 80 mg (2 tablets of Nolpaza® 40 mg). If necessary, the dose may subsequently be titrated up or down depending on gastric acid secretion levels. Doses exceeding 80 mg daily should be divided into two doses. Temporary dose increases beyond 160 mg of pantoprazole may be possible, but the duration of use should be limited only to the period required for adequate acid control.

The treatment duration for Zollinger-Ellison syndrome and other pathological conditions is not limited and depends on clinical necessity.

Patients with hepatic impairment. In patients with severe liver dysfunction, the daily dose should not exceed 20 mg (1 tablet of Nolpaza® 20 mg). Nolpaza® should not be used for H. pylori eradication in combination therapy in patients with moderate to severe hepatic impairment, as there are currently no data on the efficacy and safety of such use in this patient population.

Patients with renal impairment. Dose adjustment is not required in patients with renal impairment. Nolpaza® should not be used for H. pylori eradication in combination therapy in patients with renal impairment, as there are currently no data on the efficacy and safety of such use in this patient population.

Elderly patients do not require dose adjustment.

Children.

Nolpaza® 40 mg is indicated for children aged 12 years and older for the treatment of reflux esophagitis. The drug is not recommended for use in children under 12 years of age, as data on safety and efficacy in this age group are limited.

Overdose.

Symptoms of overdose are unknown.

Doses up to 240 mg administered intravenously over 2 minutes were well tolerated. Since pantoprazole is highly 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 treatment.

Adverse Reactions

Adverse reactions were observed in approximately 5% of patients.

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, hypokalemia.

Psychiatric disorders.

Uncommon: sleep disorders.

Rare: depression (including exacerbation).

Very rare: disorientation (including exacerbation).

Not known: hallucination, confusion (particularly in patients predisposed to such disorders, and including exacerbation of these symptoms if pre-existing).

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 (benign).

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

Not known: microscopic colitis.

Hepatobiliary disorders.

Uncommon: increased 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 (toxic epidermal necrolysis, TEN), erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special precautions"), phototoxicity, 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.

Uncommon: asthenia, fatigue, malaise.

Rare: increased body temperature, peripheral edema.

¹ Hypocalcemia and/or hypokalemia may be associated with the development of hypomagnesemia (see section "Special precautions").
² Muscle spasms as a consequence of electrolyte imbalance.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance 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 to the State Expert Centre of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions.

Store at temperatures not exceeding 30°C, in the original packaging to protect from moisture. Keep out of reach and sight of children.

Packaging.

14 tablets in a blister; 1, 2, or 4 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

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

Manufacturer's address and place of business.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.