Pangastro®

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

Composition:

Active substance: pantoprazole;

1 tablet contains 40 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 properties: yellow, oval-shaped tablets with a coating. Dimensions: approximately 11.7 × 6.0 mm.

Pharmacotherapeutic group. Drugs for 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 acting on 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 stage of 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, the drug affects acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect of the drug is the same following oral administration or intravenous injection.

Fasting gastrin levels increase during pantoprazole treatment. With short-term use, levels usually do not exceed the upper limit of normal. With long-term therapy, gastrin levels typically double. However, excessive increases have been 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 noted in rare cases during prolonged treatment. However, according to study data, the formation of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors has not been observed during human therapeutic use of the drug.

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

Pharmacokinetics.

Absorption. Pantoprazole is rapidly and completely absorbed. Maximum plasma concentration is achieved even after a single oral dose of 40 mg. On average, peak serum concentration, approximately 2–3 μg/mL, is reached within 2.5 hours after administration. Serum concentration remains stable with repeated dosing. Pharmacokinetic characteristics do not change with single or repeated administration. When administered in doses ranging from 10 mg to 80 mg, pantoprazole plasma kinetics change linearly, both after oral administration and intravenous injection. Absolute bioavailability of the tablet formulation has been established at 77%. Food intake does not affect AUC (area under the concentration–time curve), peak serum concentration, or bioavailability. Only fluctuations in the duration of the latency period increase when the drug is taken with food.

Distribution. Plasma protein binding is 98%. The volume of distribution is approximately 0.15 L/kg.

Elimination. The drug undergoes almost complete metabolic transformation in the liver. The main metabolic pathway is demethylation via CYP2C19, followed by sulfate conjugation; another metabolic pathway involves oxidation by the enzyme CYP3A4. The terminal elimination half-life is approximately 1 hour, and clearance is about 0.1 L/h/kg. Several cases of delayed elimination from the body have been observed. 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. The primary route of excretion of pantoprazole metabolites is renal (approximately 80%); the remainder is 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.

Use in special patient populations. Approximately 3% of Europeans lack functional CYP2C19 enzyme; these individuals are referred to as poor metabolizers. In such individuals, pantoprazole metabolism is likely primarily catalyzed by CYP3A4. After a single 40 mg dose, the mean AUC was approximately 6 times higher in poor metabolizers compared to individuals with functional CYP2C19 (extensive metabolizers). The mean peak concentration increased by approximately 60%. These findings do not affect pantoprazole dosing. No dosage reduction recommendations are necessary for patients with impaired renal function (including patients on hemodialysis). As in healthy volunteers, the elimination half-life of the drug in these patients remains short. Only a small amount of pantoprazole is dialyzed. Although the elimination half-life of the main metabolite slightly increases (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 of the active substance increases to 7–9 hours, and accordingly, AUC increases 5–7 times. However, peak pantoprazole plasma concentration increases only 1.5-fold compared to healthy volunteers.

A minor increase in AUC and peak concentration in elderly patients compared to younger patients is not clinically significant.

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, any component of the medicinal product, or substances contained in combination partners.

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).

HIV drugs (atazanavir). Concomitant use of PPIs with atazanavir and other HIV 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.

Coumarin anticoagulants (phenprocoumon and warfarin). Although no interaction was observed during clinical studies when pantoprazole was 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 have their prothrombin time/INR monitored when starting, stopping, or irregularly taking pantoprazole.

Methotrexate. Concomitant administration of high-dose methotrexate (e.g., 300 mg) and PPIs increases methotrexate blood levels in some patients. Patients receiving high-dose 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, glibenclamide, 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 several 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), CYP2E1 (such as ethanol), nor does it affect P-glycoprotein, which mediates digoxin absorption.

No interaction has been 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 were identified between these drugs.

Medicinal products that inhibit or induce CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, may increase the systemic exposure to pantoprazole. Dose reduction should be considered in patients requiring long-term, high-dose pantoprazole therapy or in those 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.

Interaction between medicinal products and laboratory tests.

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

Special precautions for use.

Hepatic impairment. Patients with severe liver dysfunction should have regular monitoring of liver enzymes. If liver enzyme levels increase, treatment with the medicinal product should be discontinued.

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

The use of PanGastro**®**, 20 mg tablets, for prevention of gastric and duodenal ulcers induced by long-term NSAID therapy, should be limited in patients prone to frequent ulcer relapses.

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

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 pantoprazole treatment may mask symptoms of malignant ulcer and delay diagnosis. If symptoms persist despite adequate therapy, 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 of PanGastro**®** with atazanavir is necessary, careful clinical monitoring (e.g., measurement of viral load) should be performed, along with increasing the atazanavir dose to 400 mg in combination with 100 mg ritonavir. The pantoprazole dose should not exceed 20 mg once daily.

Vitamin B12 absorption. In patients with Zollinger–Ellison syndrome and other disorders causing pathological hypersecretion requiring long-term therapy, pantoprazole, like all acid-suppressing agents, may reduce absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in patients with low body weight or risk factors during long-term therapy, or if corresponding clinical symptoms occur.

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

Gastrointestinal infections caused by bacteria. Pantoprazole, like other PPIs, may increase the number of bacteria normally present in the upper gastrointestinal tract. Treatment with the medicinal product 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. 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 "Undesirable effects"). 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.

Patients requiring long-term therapy, or those receiving PPIs in combination with digoxin or other medicinal products 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 treatment (more than one year) with high doses of PPIs may slightly increase the risk of fractures of the hip, wrist, and spine, particularly in elderly patients or in the presence of other risk factors. Observational studies suggest that PPI use may increase the overall risk of fractures by 10–40%. Patients at risk of osteoporosis should receive treatment according to current clinical guidelines and should consume adequate amounts of vitamin D and calcium.

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

Severe cutaneous adverse reactions. Severe cutaneous adverse reactions associated with pantoprazole use, with unknown frequency (see section "Undesirable effects"), potentially life-threatening or fatal, such as erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported. Patients should be informed about the signs and symptoms of these skin reactions, and closely monitored for their development. If signs or symptoms suggestive of these reactions occur, pantoprazole should be discontinued immediately and alternative therapy considered.

Subacute cutaneous lupus erythematosus (SCLE). PPIs are associated with very rare cases of SCLE. In case of skin lesions, particularly photosensitive lesions, especially when accompanied by arthralgia, patients should seek immediate medical attention, and healthcare professionals should consider discontinuation of pantoprazole. Previous treatment with PPIs may increase the risk of developing SCLE upon subsequent use of other PPIs.

Effect on laboratory tests.

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

Use during pregnancy or breastfeeding.

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

Breastfeeding. Animal studies have shown excretion of pantoprazole into breast milk. Data on excretion of pantoprazole into human breast milk are limited, but such excretion has been reported. Risk to newborns/infants cannot be excluded. The decision to discontinue breastfeeding or to discontinue/abstain from 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 influence 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 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, 1 hour before a meal, with water.

Adults and children aged 12 years and older.

Treatment of reflux esophagitis.

The recommended dose is 1 tablet of PanGastro**®** 40 mg once daily. In individual cases, the dose may be doubled (2 tablets of PanGastro**®** 40 mg per day), especially if there is no response to other medications used for the treatment of reflux esophagitis.

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

Adults.

Eradiation of H. pylori in combination with two antibiotics.

In adult patients with gastric or duodenal ulcer and a positive H. pylori test, eradication of the microorganism should be achieved using combination therapy. Depending on microbial sensitivity, the following therapeutic regimens may be prescribed for eradication of Helicobacter pylori in adults:

a) 1 tablet of PanGastro**®** 40 mg twice daily

• 1 g amoxicillin twice daily + 500 mg clarithromycin twice daily;

b) 1 tablet of PanGastro**®** 40 mg twice daily

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

c) 1 tablet of PanGastro**®** 40 mg twice daily

• 1 g amoxicillin twice daily + 400–500 mg metronidazole (or 500 mg tinidazole)
  twice daily.

When using combination therapy for H. pylori eradication, the second dose of the drug should be taken in the evening, 1 hour before a meal. The duration of treatment is 7 days and may be extended for another 7 days (total treatment duration—no more than 2 weeks).

When prescribing therapy, national guidelines regarding bacterial resistance and appropriate use of antibacterial agents should be taken into account.

If continued treatment with pantoprazole is indicated to ensure ulcer healing, dosing recommendations for gastric and duodenal ulcers should be considered. If combination therapy is not indicated, e.g., in patients with a negative H. pylori test, monotherapy with PanGastro**®** at the dosage specified below should be prescribed.

Treatment of gastric ulcer.

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

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

Treatment of duodenal ulcer.

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

Treatment of duodenal ulcer usually requires 2 weeks. If this is insufficient, 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 PanGastro**®** 40 mg). If necessary, the dose may subsequently be titrated up or down depending on gastric acid secretion parameters. If the daily dose exceeds 80 mg, it should be divided into two doses. A temporary increase in dose above 160 mg of pantoprazole may be possible, but the duration of use should be limited only to the period required for adequate control of acid secretion.

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

Patients with severe hepatic impairment should not exceed a daily dose of 20 mg (1 tablet of PanGastro**®** 20 mg). Patients with moderate to severe hepatic impairment should not be treated with PanGastro**®** for H. pylori eradication in combination therapy, as there are no data on the efficacy and safety of such use. Additionally, liver enzymes should be monitored in these patients.

Patients with renal impairment do not require dose adjustment. PanGastro**®** should not be used for H. pylori eradication in combination therapy in patients with renal impairment, as there are no data on the efficacy and safety of such use.

Elderly patients do not require dose adjustment.

Children.

PanGastro**®** 40 mg is indicated for children aged 12 years and older for the treatment of reflux esophagitis. The drug is not recommended for 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. Pantoprazole is extensively protein-bound and is not completely removed by dialysis.

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

Adverse Reactions

Adverse reactions occurred in approximately 5% of patients. The most frequently observed adverse reactions were diarrhea and headache (approximately 1%).

Undesirable effects are classified by frequency of occurrence as follows: 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), and frequency not known (frequency cannot be estimated from the 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: paraesthesia.

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 rash, 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 cramps² as a consequence of electrolyte imbalance.

Renal and urinary disorders

Frequency not known: tubulointerstitial nephritis (with potential 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 the development of hypomagnesemia (see section "Special precautions").

² Muscle cramps 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, as well as their legal representatives, are encouraged to report all 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 reach of children.

Packaging. Blister packs containing 7 or 14 tablets; 2 or 4 blisters of 7 tablets, or 1 or 2 blisters of 14 tablets per cardboard box.

Prescription status. Prescription only.

Manufacturer.

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

Manufacturer's address and place of business.

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