INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NOLOPAZA® (NOLPAZA®)

Composition:

Active substance: pantoprazole;

One gastro-resistant tablet contains 20 mg 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, methacrylate copolymer dispersion, sodium lauryl sulfate, polysorbate 80, talc, macrogol 6000.

Pharmaceutical form. Gastro-resistant tablets.

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

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

Pharmacological Properties

Pharmacodynamics

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 an acidic environment, specifically within parietal cells, where it inhibits the H+-K+-ATPase enzyme, thereby blocking the final step of gastric hydrochloric acid production. This inhibition is dose-dependent and suppresses both basal and stimulated acid secretion.

Treatment with 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. The increase in gastrin secretion is reversible. Since pantoprazole binds to the enzyme distal to the cellular receptor, it can inhibit acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The efficacy of the drug is equivalent following either oral administration or intravenous infusion.

Administration of pantoprazole increases fasting gastrin levels. With short-term use, these levels generally remain within the upper normal range. During long-term treatment, gastrin levels typically double. Marked elevation occurs only in isolated cases. As a consequence, a slight or moderate increase in the number of gastric enterochromaffin-like cells (ECL cells) (adenomatoid hyperplasia) may be observed in a small number of cases during prolonged therapy. However, to date, studies have not shown the development of neuroendocrine tumor precursor cells observed in animal experiments to occur in humans. Nevertheless, with long-term treatment (more than 1 year), the potential influence of pantoprazole on thyroid gland endocrine parameters cannot be excluded.

During treatment with antisecretory agents, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels rise. Elevated CgA levels may interfere with diagnostic tests 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 prior to measuring CgA levels. This allows CgA levels to return to the normal range, as they may be falsely elevated following PPI therapy.

Pharmacokinetics

Pantoprazole is rapidly absorbed, and maximum plasma concentration is achieved even after a single 40 mg dose. On average, maximum plasma concentration of 2–3 μg/mL is reached within 2.5 hours after administration and remains consistent after repeated dosing. The volume of distribution is approximately 0.15 L/kg, and clearance is approximately 0.1 L/h/kg.

The elimination half-life is approximately 1 hour. In some cases, elimination time may be prolonged. Due to the specific binding of pantoprazole to the proton pump of parietal cells, the half-life does not correlate with the longer duration of action.

Pharmacokinetics are unchanged after single or repeated administration. At doses ranging from 10 to 80 mg, the plasma kinetics of pantoprazole are linear, both after oral and intravenous administration.

Protein binding of pantoprazole to plasma proteins is approximately 98%. The drug is almost entirely metabolized in the liver. The primary route of elimination is renal—approximately 80% of pantoprazole metabolites are excreted in urine; the remainder is excreted in feces. The main metabolite in both plasma and urine is desmethylpantoprazole sulfate. The half-life of the main metabolite (approximately 1.5 hours) is slightly longer than that of pantoprazole.

Bioavailability. After oral administration, pantoprazole is completely absorbed. The absolute bioavailability of the tablet is approximately 77%. Food intake has no effect on the area under the plasma concentration-time curve (AUC), maximum plasma concentration, or bioavailability; only a slight delay in onset of action occurs.

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

Characteristics in Special Patient Populations

Poor metabolizers. Approximately 3% of Europeans have low functional activity of the CYP2C19 enzyme and are referred to as poor metabolizers. In these individuals, pantoprazole metabolism is likely primarily catalyzed by CYP3A4. After a single 40 mg dose, the mean plasma concentration-time AUC was approximately 6 times higher in poor 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.

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

In patients with liver cirrhosis (Child-Pugh classes A and B), the elimination half-life increases to 7–9 hours, resulting in a 5- to 7-fold increase in AUC and a 1.5-fold increase in maximum plasma concentration of pantoprazole compared to healthy individuals.

A slight increase in AUC and maximum plasma concentration of pantoprazole in elderly volunteers compared to younger individuals is not clinically significant.

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

Children. After a single oral dose of 20 or 40 mg pantoprazole, AUC and Cmax values in children aged 5 to 16 years were within the range observed in adults. After a single intravenous dose 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 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.

Symptomatic treatment of gastroesophageal reflux disease.
Long-term treatment and prevention of relapses of reflux esophagitis.

Adults.

Prevention of gastric and duodenal ulcer formation associated with the use of non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) in high-risk patients who require long-term NSAID therapy.

Contraindications.

Hypersensitivity to pantoprazole, benzimidazole derivatives, or to any other 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 hydrochloric 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 warnings and 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 pathological 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 blood levels of methotrexate when high-dose methotrexate (e.g., 300 mg) is administered concomitantly with proton pump inhibitors in some patients. Patients receiving high-dose methotrexate, such as those with cancer or psoriasis, should temporarily discontinue pantoprazole therapy.

Studies on 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 CYP3A4.

Studies with medicinal products 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 by 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 (such as caffeine and theophylline), CYP2C9 (e.g., piroxicam, diclofenac, naproxen), CYP2D6 (e.g., metoprolol), CYP2E1 (e.g., ethanol), or does not affect P-glycoprotein involved in digoxin absorption.

No interactions were observed with concomitantly administered antacids.

Specific interaction studies have been conducted with pantoprazole and certain antibiotics (clarithromycin, metronidazole, amoxicillin) when administered together. 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 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 by 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. An alternative testing method should be considered to confirm test results.

Special precautions for use.

Patients with impaired liver function

In patients with severe impairment of liver function, regular monitoring of liver enzymes is required during treatment with the drug, especially during long-term use. If liver enzyme levels increase, treatment must be discontinued.

Concomitant use with NSAIDs

The use of Nolpaza® 20 mg gastro-resistant tablets for prevention of gastric and duodenal ulcers caused by long-term NSAID therapy should be limited in patients prone to frequent ulcer relapses.

Assessment of risk level should take into account individual risk factors, including age (>65 years), history of gastric or duodenal ulcer, and gastrointestinal bleeding.

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 in the presence of risk factors for reduced vitamin B12 (cyanocobalamin) absorption, particularly during long-term treatment or when corresponding clinical symptoms are present.

Long-term treatment

Patients undergoing treatment for more than 1 year should remain under continuous medical supervision.

Malignant gastric tumors
Symptomatic response to pantoprazole may mask symptoms of malignant gastric tumors and delay their diagnosis. In the presence of alarm symptoms (e.g., significant weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena), or suspicion or presence of gastric ulcer, malignancy must be ruled out.

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

Hypomagnesemia
Rare cases of severe hypomagnesemia have been reported in patients treated with proton pump inhibitors (PPIs), such as pantoprazole, for at least 3 months, mostly after one year of therapy. Serious clinical manifestations of hypomagnesemia may develop insidiously, including 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), patients' condition improved in most cases after magnesium replacement therapy and discontinuation of PPI treatment.

In patients requiring long-term therapy, and in those receiving PPIs concomitantly with digoxin or other drugs that may cause hypomagnesemia (e.g., diuretics), serum magnesium levels should be measured before initiating PPI therapy 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, particularly in elderly patients or those with other risk factors. Observational studies suggest 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 ensure adequate intake of vitamin D and calcium.

Gastrointestinal infections caused by bacteria

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

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions, including erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported during pantoprazole use, 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 must be discontinued immediately and alternative treatment options considered.

Subacute cutaneous lupus erythematosus (SCLE)
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 during previous therapy with proton pump inhibitors may increase the risk of recurrence when other proton pump inhibitors are used.

Effect on laboratory test results

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

Information on 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 has been observed in animal studies. As a precautionary measure, use of Nolpaza® in pregnant women should be avoided.

Breastfeeding
Animal studies have shown excretion of pantoprazole into breast milk. There is limited data on excretion of pantoprazole into human breast milk, but such excretion has been reported. Risk to newborns/infants cannot be excluded. The 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 influence reaction speed when driving or operating machinery

Pantoprazole has no effect or has a negligible effect on the ability to drive or operate machinery. However, the possible occurrence of adverse reactions such as dizziness and visual disturbances should be taken into account (see section "Adverse reactions"). In such cases, driving or operating machinery should be avoided.

Method of Administration and Dosage

Nolpaza®, gastro-resistant tablets of 20 mg, should be taken whole, one hour before a meal, without chewing or crushing, with water.

Recommended Dosage

Adults and children aged 12 years and older

Symptomatic treatment of gastroesophageal reflux disease (GERD).

The recommended dose is 20 mg (1 tablet) of Nolpaza® once daily. Symptoms of heartburn usually resolve within 2–4 weeks. If this period is insufficient, treatment may be continued for an additional 4 weeks. After symptom resolution, recurrences can be managed by taking 20 mg of the drug as needed.

Long-term treatment and prevention of relapses of reflux esophagitis.

For long-term maintenance therapy, the recommended dose is 20 mg (1 tablet) of Nolpaza® once daily. During disease exacerbations, the dose may be increased up to 40 mg daily. In such cases, administration of Nolpaza® 40 mg tablets is recommended. After resolution of the relapse, the dose may be reduced again to 20 mg once daily.

Adults

Prevention of gastric and duodenal ulcers associated with long-term use of non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) in patients at risk who require prolonged NSAID therapy.

The recommended dose is 20 mg (1 tablet) of Nolpaza® once daily.

Hepatic impairment. In patients with severe hepatic impairment, the dose should not exceed 20 mg (1 tablet) per day.

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

Elderly patients do not require dose adjustment.

Children

The drug should not be used in children under 12 years of age.

Overdose

Symptoms of overdose are unknown.

Doses up to 240 mg administered intravenously over 2 minutes have been well tolerated. Since pantoprazole is highly protein-bound, it is not readily dialyzable.

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), 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"), hypocalcemia\textsuperscript{1}, hypokalemia.

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 pre-existing).

Nervous system disorders.

Uncommon: headache, dizziness.

Rare: taste disturbances.

Not known: paraesthesia.

Eye disorders.

Rare: visual disturbances/blurred vision.

Gastrointestinal disorders.

Common: polyps of fundic glands (benign).

Uncommon: diarrhea, nausea, vomiting, abdominal distension, 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, toxic epidermal necrolysis (TEN), Lyell's syndrome, 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 spasms\textsuperscript{2}.

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.

\textsuperscript{1}Hypocalcemia and/or hypokalemia may be associated with the development of hypomagnesemia (see section "Special precautions").

\textsuperscript{2}Muscle spasms as a consequence of electrolyte imbalance.

Reporting of 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. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance System at: 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 of children.

Packaging.

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