Pangastro®

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

Composition:

Active substance: pantoprazole;

One tablet contains 20 mg of pantoprazole (as pantoprazole sodium sesquihydrate);

Excipients: anhydrous sodium carbonate, microcrystalline cellulose, crospovidone (type A), hydroxypropylcellulose, colloidal anhydrous silicon dioxide, calcium stearate;

Coating: Opadry Yellow (hypromellose, titanium dioxide (E 171), polyethylene glycol 400, quinoline yellow (E 104), iron oxide yellow (E 172), Ponceau 4R (E 124)), methacrylic acid copolymer (type A), polysorbate 80, sodium lauryl sulfate.

Pharmaceutical form. Gastro-resistant tablets.

Main physicochemical characteristics: yellow, oval-shaped, coated tablets. Dimensions: approximately 8.9 × 4.6 mm.

Pharmacotherapeutic group. Drugs for the treatment of acid-related disorders. Proton pump inhibitors. ATC code A02BC02.

Pharmacological Properties

Pharmacodynamics

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

Pantoprazole is converted into its active form in the acidic canaliculi of parietal cells, where it inhibits the enzyme H+-K+-ATPase, i.e., the final step in hydrochloric acid production. This inhibition is dose-dependent and affects both basal and stimulated gastric acid secretion. In most patients, symptom relief occurs within 2 weeks. Like other proton pump inhibitors (PPIs) and H2-receptor antagonists, pantoprazole reduces gastric acidity, resulting in a proportional increase in gastrin secretion. The increase in gastrin levels is reversible. Since pantoprazole binds to enzymes distant from cellular receptors, its effect on acid secretion is independent of stimulation by other substances (acetylcholine, histamine, gastrin). The effect of the drug is the same following oral administration or intravenous infusion.

Fasting gastrin levels increase during pantoprazole therapy. With short-term use, levels usually remain within the upper normal range. With prolonged treatment, gastrin levels typically double. However, marked increases were observed only in isolated cases. As a result, minor or moderate increases in the number of enterochromaffin-like (ECL) cells in the stomach (similar to adenomatoid hyperplasia) have been observed in isolated cases during long-term therapy. However, according to study data, the formation of precursor cells of neuroendocrine tumors (atypical hyperplasia) or gastric neuroendocrine tumors has not been observed during human treatment with this drug.

Based on animal studies, an effect of long-term (more than 1 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. Additionally, 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 PPI treatment 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, as they may be falsely elevated after PPI treatment.

Pharmacokinetics

Absorption. Pantoprazole is rapidly absorbed, and maximum plasma concentration is achieved after a single oral dose of 20 mg. On average, peak serum concentration of approximately 1–1.5 µg/mL is reached within 2.5 hours after administration; plasma concentrations remain stable with repeated dosing.

The elimination half-life is approximately 1 hour, and clearance is 0.1 L/h/kg. There have been several reports of delayed elimination of the substance. Due to the specific binding of pantoprazole to proton pumps in parietal cells, the elimination half-life does not correlate with the duration of pharmacological effect (acid secretion inhibition), which is considerably longer.

Pharmacokinetic characteristics do not change with single or repeated administration. With doses ranging from 10 mg to 80 mg, pantoprazole plasma kinetics are linear both after oral administration and intravenous infusion.

Plasma protein binding is 98%. The volume of distribution is approximately 0.15 L/kg. The drug undergoes almost complete hepatic metabolism. The main metabolic pathway is demethylation via CYP2C19, followed by sulfation; another metabolic pathway involves oxidation via CYP3A4. The primary route of elimination of pantoprazole metabolites is renal (approximately 80%), with the remainder excreted in feces. The main metabolite in both serum and urine is desmethylpantoprazole sulfate conjugate. The elimination half-life of the main metabolite (1.5 hours) is only slightly longer than that of pantoprazole.

Bioavailability. Pantoprazole is completely absorbed after oral administration. The absolute bioavailability of the tablet formulation is 77%. Food intake does not affect AUC (area under the concentration–time curve), peak serum concentration, or bioavailability. Only the variability in the latency period duration increases when taken with food.

Characteristics in Special Patient Populations

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

Dose reduction of pantoprazole is not required in patients with impaired renal function, including those on hemodialysis. As in healthy volunteers, the drug's elimination half-life in these patients is short. Only a small amount of pantoprazole is dialyzed. Although the elimination 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 liver cirrhosis (Child-Pugh class A and B), the elimination half-life of the active substance increases to 3–6 hours and AUC correspondingly increases 3–5 times, the maximum plasma concentration of pantoprazole increases only 1.3-fold compared to healthy volunteers.

The slight increase in AUC and peak concentration observed in elderly patients compared to younger patients is not clinically significant.

Children. After single oral doses of 20 or 40 mg of pantoprazole, AUC and Cmax values in children aged 5 to 16 years were within the range observed in adults. After single intravenous administration of pantoprazole at doses of 0.8 or 1.6 mg/kg in children aged 2 to 16 years, no significant relationship between pantoprazole clearance and patient age or body weight was observed. AUC and volume of distribution were consistent with 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 patients at risk who require long-term NSAID therapy.

Contraindications.

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

Interaction with other medicinal products and other types of interactions.

Effect of pantoprazole on the absorption of other medicinal products. 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 (PPIs) with atazanavir and other antiretroviral drugs whose absorption is pH-dependent may lead to a significant reduction in their bioavailability and affect their efficacy. Therefore, concomitant use of PPIs with atazanavir is not recommended.

In cases where concomitant use of HIV protease inhibitors with PPIs 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). Despite the absence of interactions observed during clinical trials when co-administered with phenprocoumon and warfarin, isolated cases of changes in INR (international normalized ratio) have been reported in the post-marketing period. Therefore, patients receiving coumarin anticoagulants (e.g., phenprocoumon and warfarin) should be monitored for prothrombin time/INR when starting, stopping, or irregularly taking pantoprazole.

Methotrexate. There have been reports that concomitant use of high-dose methotrexate (e.g., 300 mg) and PPIs 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 CYP3A4. Studies with drugs also metabolized through these pathways—such as carbamazepine, diazepam, glyburide, nifedipine, phenprocoumon, and oral contraceptives containing levonorgestrel and ethinylestradiol—did not reveal clinically significant interactions.

Interaction between pantoprazole and other medicinal products metabolized by the same enzyme system cannot be excluded.

Results from multiple studies on potential interactions indicate that pantoprazole does not affect the metabolism of active substances metabolized by CYP1A2 (such as caffeine, theophylline), CYP2C9 (e.g., piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), or CYP2E1 (such as ethanol), nor does it affect P-glycoprotein, which mediates digoxin absorption.

No interactions were observed with concomitantly administered antacids.

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

Medicinal products that inhibit or induce CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, may lead to increased systemic exposure to pantoprazole. A dose reduction should be considered for patients requiring long-term high-dose pantoprazole therapy or those with impaired liver function.

Enzyme inducers affecting CYP2C19 and CYP3A4, such as rifampicin and products containing St. John’s wort (Hypericum perforatum), may lead to decreased plasma concentrations of PPIs metabolized through these enzyme systems.

Interaction between medicinal products and laboratory tests.

False-positive results in certain urine screening tests for tetrahydrocannabinol have been reported in patients taking pantoprazole. Alternative confirmatory testing methods should be considered to confirm positive results.

Special precautions for use.

Hepatic impairment. In patients with severe hepatic impairment, regular monitoring of liver enzymes is required, particularly during long-term treatment. If liver enzyme levels increase, treatment with the drug should be discontinued.

Concomitant use with nonsteroidal anti-inflammatory drugs (NSAIDs).

The use of PanGastro® 20 mg tablets for the prevention of gastric and duodenal ulcers caused by long-term NSAID therapy should be limited to patients who are prone to frequent ulcer recurrences.

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

Presence of alarm symptoms. In the presence of alarm symptoms (e.g., significant weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena), and in cases of suspected or confirmed gastric ulcer, malignancy must be ruled out, as treatment with pantoprazole may mask symptoms of malignant ulcer and delay diagnosis. If symptoms persist during adequate treatment, further investigation is required.

Concomitant use with atazanavir. Proton pump inhibitors (PPIs) are not recommended for concomitant use with atazanavir (see section "Interaction with other medicinal products and other forms of interaction"). If combination therapy with PanGastro® and atazanavir is necessary, close clinical monitoring (e.g., measurement of viral load) should be performed, along with increasing the atazanavir dose to 400 mg co-administered with 100 mg ritonavir. The pantoprazole dose should not exceed 20 mg daily.

Vitamin B12 absorption. Pantoprazole may reduce absorption of vitamin B12 (cyanocobalamin), potentially leading to hypo- or achlorhydria. This should be considered during long-term treatment, particularly in patients with low body weight or risk factors during prolonged therapy, or if corresponding clinical symptoms occur.

Long-term treatment. Patients undergoing long-term treatment, especially exceeding one year, should remain under continuous medical supervision.

Gastrointestinal tract infections caused by bacteria. Pantoprazole, like other 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.

Hypomagnesemia. Rare cases of severe hypomagnesemia have been reported in patients receiving proton pump inhibitors (PPIs), such as pantoprazole, for at least three months, and in most cases after one year of treatment. Serious clinical manifestations of hypomagnesemia, such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia, may develop insidiously. Hypomagnesemia may lead to the development of hypocalcemia and/or hypokalemia (see section "Adverse reactions"). In cases of hypomagnesemia (and hypocalcemia and/or hypokalemia associated with hypomagnesemia), the condition of most patients improved after magnesium replacement therapy and discontinuation of PPIs.

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

Bone fractures. Long-term (more than one year) high-dose treatment with proton pump inhibitors may slightly 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 should consume adequate amounts of vitamin D and calcium.

Patients should not use any other PPI or H2-receptor antagonist concomitantly.

Patients should be informed that pantoprazole tablets are not intended for immediate symptom relief. Symptom improvement may occur approximately one day after starting pantoprazole treatment, but up to 7 days may be required for complete resolution of heartburn symptoms. Patients should not use pantoprazole as a preventive measure.

Severe cutaneous adverse reactions. Serious cutaneous adverse reactions associated with pantoprazole use, with unknown frequency, have been reported (see section "Adverse reactions"), which may be life-threatening or fatal, such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Patients should be informed about the signs and symptoms of these skin reactions, and careful monitoring for their development is required. If signs or symptoms suggestive of these reactions occur, pantoprazole should be discontinued immediately and alternative treatment considered.

Subacute cutaneous lupus erythematosus (SCLE). PPIs are associated with very rare cases of SCLE. In cases of skin lesions, particularly those occurring after sun exposure, and if accompanied by arthralgia, patients should seek immediate medical attention, and healthcare professionals should consider discontinuing pantoprazole. Prior treatment with PPIs may increase the risk of developing SCLE upon subsequent use of other PPIs.

Effect on laboratory tests.

Elevated chromogranin A levels may interfere with diagnostic testing for neuroendocrine tumors. To avoid this effect, pantoprazole treatment should be discontinued at least 5 days before chromogranin A measurement. If chromogranin A and gastrin levels do not return to reference ranges after initial laboratory testing, these parameters should be re-measured 14 days after discontinuation of PPI therapy.

Use during pregnancy or breastfeeding.

Pregnancy. Available data on the use of the drug in pregnant women (approximately 300–1000 reports on pregnancy outcomes) indicate no embryonal or fetal/neonatal toxicity of the drug. Embryotoxicity was observed in animal reproductive studies. The potential risk in humans is unknown. As a precautionary measure, the use of the drug in pregnant women should be avoided.

Breastfeeding period. Animal studies have shown excretion of pantoprazole into breast milk. Data are available on the excretion of pantoprazole into human breast milk. Risk to newborns/infants cannot be excluded. The decision to continue or discontinue breastfeeding or to continue or discontinue treatment with PanGastro® should be made taking into account the benefit of breastfeeding for the child and the benefit of treatment with PanGastro® for the woman.

Fertility. Pantoprazole did not impair fertility in animal studies.

Ability to affect reaction speed when driving or operating machinery.

No negative effects have been observed; however, the possibility of adverse effects such as dizziness and blurred vision should be considered. If such reactions occur, patients should refrain from driving or engaging in other potentially hazardous activities requiring high concentration and rapid psychomotor responses.

Method of Administration and Dosage

PanGastro**®**, gastro-resistant tablets, should be taken whole, without chewing or crushing, one hour before meals, 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 PanGastro**®** 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 on an "as needed" basis using 20 mg of the drug. Long-term therapy should be considered if adequate symptom control is not achieved with on-demand treatment.

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

For long-term maintenance therapy, the recommended dose is 20 mg (1 tablet) of PanGastro**®** once daily. During disease exacerbations, the dose may be increased to 40 mg daily. In such cases, PanGastro**®** 40 mg tablets are 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 NSAID use in high-risk patients requiring long-term NSAID therapy.

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

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

Renal impairment. Dose adjustment is not required in patients with renal impairment.

Elderly patients do not require dose adjustment.

Pediatric population. The drug is not recommended for children under 12 years of age due to limited data on safety and efficacy in this age group.

Children.

PanGastro**®** should not be administered to children under 12 years of age.

Overdose.

Symptoms of overdose are unknown.

Doses up to 240 mg administered intravenously over 2 minutes were well tolerated. Pantoprazole is highly protein-bound and is not completely removed by dialysis.

In case of overdose with clinical signs of intoxication, symptomatic and supportive treatment should be administered.

Adverse Reactions

Adverse reactions have been observed in approximately 5% of patients. The most frequently reported adverse reactions are diarrhea and headache (approximately 1%).

Undesirable effects are classified by frequency of occurrence into the following categories: very common (> 1/10), common (> 1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency 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.

Frequency not known: hyponatremia, hypomagnesemia, hypocalcemia¹ associated with hypomagnesemia, hypokalemia¹.

Psychiatric disorders

Uncommon: sleep disorders.

Rare: depression (with complications).

Very rare: confusion (with complications).

Frequency not known: hallucinations; mental confusion (particularly in patients predisposed to such disorders, and exacerbation of these symptoms if already present).

Nervous system disorders

Uncommon: headache, dizziness.

Rare: taste disturbances.

Frequency not known: paresthesia.

Eye disorders

Rare: visual disturbances/blurred vision.

Gastrointestinal disorders

Common: fundic gland polyps of the stomach.

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

Frequency not known: microscopic colitis.

Hepatobiliary disorders

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

Rare: increased bilirubin levels.

Frequency not known: hepatocellular injury, jaundice, hepatocellular failure.

Skin and subcutaneous tissue disorders

Uncommon: skin rashes, exanthema, pruritus.

Rare: urticaria, angioneurotic edema.

Very rare: Stevens-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), erythema multiforme, photosensitivity, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Sudden onset of urticaria indicates an allergic reaction to amoxicillin and requires immediate discontinuation of therapy.

Frequency not known: subacute cutaneous lupus erythematosus (see section "Special precautions").

Musculoskeletal and connective tissue disorders

Uncommon: fracture of the femur, wrist, or spine.

Rare: arthralgia, myalgia.

Frequency not known: muscle spasms² as a consequence of electrolyte imbalance.

Renal and urinary disorders

Frequency not known: tubulointerstitial nephritis (with possible progression to 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 hypomagnesemia (see section "Special precautions").

² Muscle spasms as a consequence of electrolyte imbalance.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system (https://aisf.dec.gov.ua).

Shelf life. 3 years.

Storage conditions.

No special storage conditions required. Keep out of the reach of children.

Packaging. 7 or 14 tablets per blister; 2 or 4 blisters containing 7 tablets each, or 1 or 2 blisters containing 14 tablets, in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

1. Lek pharmaceutical company d.d.
2. Lek S.A.

Manufacturer's address and location of operations.

1. Verovškova 57, Ljubljana 1526, Slovenia or Trimojce 2D, 9220 Lendava, Slovenia.
2. Domaniewska 50C, Warsaw, 02-672, Poland or Podlipie 16, Strzykow, 95-010, Poland.