| Pharmaceutical form. Enteric-coated tablets. Main physicochemical properties: yellow, oval-shaped tablets. Pharmacotherapeutic group. Drugs for treatment of acid-related disorders. Proton pump inhibitors. ATC code A02BC02. Pharmacological properties. Pharmacodynamics. Mechanism of action. Pantoprazole is a substituted benzimidazole that inhibits gastric acid secretion by specifically blocking proton pumps in parietal cells. Pantoprazole is transformed into its active form in the acidic environment of parietal cells, where it inhibits the H+-K+-ATPase enzyme, thereby blocking the final step of gastric hydrochloric acid production. The inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. Most patients are relieved of symptoms within 2 weeks. Use of pantoprazole, like 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 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. Use of pantoprazole increases fasting gastrin levels. With short-term treatment, gastrin levels in most cases do not exceed the upper limit of normal. With long-term treatment, gastrin levels increase approximately twofold in most cases. Marked increases occur only rarely. As a consequence, mild or moderate increases in specific endocrine (ECL) cells in the stomach (similar to adenomatoid hyperplasia) may occasionally be observed during prolonged treatment. However, according to available studies, development of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors, as observed in animal studies, has not been reported in humans. Based on animal studies, a potential effect of long-term (more than one year) pantoprazole treatment on thyroid endocrine parameters cannot be completely ruled out. During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to reduced gastric acidity, chromogranin A (CgA) levels rise. Elevated CgA levels may affect diagnostic test results for neuroendocrine tumors. Published data indicate that PPI treatment should be discontinued 5–14 days before measuring CgA levels. This allows CgA levels to return to normal ranges, which may otherwise 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 about 1–1.5 µg/mL is reached within 2–2.5 hours after administration; concentrations remain stable after repeated dosing. Pharmacokinetic properties do not change after single or repeated doses. In the dose range of 10–80 mg, pantoprazole pharmacokinetics in plasma remain linear, both after oral administration and intravenous infusion. Absolute bioavailability of the 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. Protein binding of pantoprazole in serum is about 98%. Volume of distribution is approximately 0.15 L/kg. Biotransformation. 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. Terminal half-life is about 1 hour, and clearance is 0.1 L/h/kg. Several cases of delayed elimination have been observed. Due to the specific binding of pantoprazole to proton pumps in parietal cells, the elimination half-life does not reflect the much longer duration of action (acid secretion inhibition). The majority of pantoprazole metabolites are excreted in urine (about 80%), the remainder in feces. The main metabolite in both serum and urine is desmethylpantoprazole sulfate conjugate. The half-life of the main metabolite (about 1.5 hours) is slightly longer than that of pantoprazole. Special patient groups. Slow metabolizers. Approximately 3% of Europeans have low functional activity of the CYP2C19 enzyme; these individuals are called slow metabolizers. In such individuals, pantoprazole metabolism is likely primarily catalyzed by the CYP3A4 enzyme. After a single 40 mg dose of pantoprazole, the mean area under the plasma concentration-time curve was approximately 6 times higher in slow metabolizers compared to individuals with functionally active CYP2C19 (fast metabolizers). Peak plasma concentration increased by about 60%. These results do not affect pantoprazole dosing. Renal impairment. No dosage adjustment recommendations are required for pantoprazole in patients with impaired renal function (including dialysis patients). As in healthy individuals, the elimination half-life of pantoprazole is short. Only very small amounts of pantoprazole are dialyzed. Despite the moderately prolonged half-life of the main metabolite (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 3–6 hours and AUC increases 3–5 times, peak serum concentration increases only slightly—by 1.3 times compared to healthy volunteers. Elderly patients. Slight increases in AUC and Cmax in elderly volunteers compared to younger volunteers are not clinically significant. Children. After a single oral dose of 20 or 40 mg pantoprazole, AUC and Cmax 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 in children aged 2 to 16 years, no significant relationship was observed between pantoprazole clearance and patient age or body weight. AUC and volume of distribution corresponded to data obtained in adult studies. Clinical characteristics. Indications. Adults and children aged 12 years and older. - Gastroesophageal reflux disease (GERD) with esophagitis.
Adults. - Helicobacter pylori (H. pylori) eradication 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 excipient of the medicinal product. Interaction with other medicinal products and other forms of interaction. Medicinal products whose absorption depends on pH. 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 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 depends on intragastric pH, is not recommended due to significantly reduced bioavailability (see section "Special warnings and precautions for use"). When concomitant use of HIV protease inhibitors with proton pump inhibitors cannot be avoided, careful clinical monitoring (e.g., viral load) is recommended. The daily dose of pantoprazole should not exceed 20 mg. Dose adjustment of HIV protease inhibitors may be necessary. Coumarin anticoagulants (phenprocoumon and warfarin). Concomitant use of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon, or INR (international normalized ratio). However, increased INR and prolonged prothrombin time have been reported in patients receiving concomitant PPIs and warfarin or phenprocoumon. Increased INR and prolonged prothrombin time may lead to pathological bleeding and even death. Monitoring of INR and prothrombin time is necessary when these drugs are used together. Methotrexate. Concurrent use of high-dose methotrexate (e.g., 300 mg) and proton pump inhibitors has been reported to increase methotrexate blood levels in some patients. Patients receiving high-dose methotrexate, such as those with cancer or psoriasis, should temporarily discontinue pantoprazole treatment. Other interactions. Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation via CYP2C19, with other pathways including oxidation via CYP3A4. Studies with drugs also metabolized via these pathways—such as carbamazepine, diazepam, glyburide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—did not reveal clinically significant interactions. Interaction between pantoprazole and other drugs metabolized via the same enzyme system cannot be excluded. Results from multiple interaction studies indicate that pantoprazole does not affect the metabolism of active substances metabolized via CYP1A2 (e.g., caffeine, theophylline), CYP2C9 (e.g., piroxicam, diclofenac, naproxen), CYP2D6 (e.g., metoprolol), CYP2E1 (e.g., ethanol), nor does it affect P-glycoprotein associated with digoxin absorption. No interaction was observed with concomitantly administered antacids. Interaction studies between pantoprazole and certain concomitantly administered antibiotics (clarithromycin, metronidazole, amoxicillin) have been conducted. No clinically significant interactions were observed between these drugs. Medicinal products that inhibit or induce CYP2C19. CYP2C19 inhibitors, such as fluvoxamine, may increase systemic exposure to pantoprazole. Dose reduction should be considered for patients on long-term, high-dose pantoprazole therapy and for patients with hepatic impairment. 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 test results. False-positive results in certain urine screening tests for tetrahydrocannabinol have been reported in patients taking pantoprazole. Alternative testing methods should be considered to confirm results. Special warnings and precautions for use. Hepatic impairment. In patients with severe hepatic impairment, liver enzyme levels should be monitored regularly, especially during long-term treatment. If liver enzyme levels increase, treatment should be discontinued (see section "Dosage and administration"). Concomitant use with NSAIDs. The medicinal product Espa-prazol®, 40 mg tablets, should be used for prevention of gastric and duodenal ulcers due to long-term NSAID use only in patients prone to frequent gastric and duodenal ulcer recurrences. Risk assessment should consider individual factors, including age (>65 years), history of gastric or duodenal ulcer, and gastrointestinal bleeding. Gastric malignancies. Symptomatic response to pantoprazole may mask symptoms of gastric malignancies and delay diagnosis. In cases of alarm symptoms (e.g., significant weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena), and in the presence of or suspicion of gastric ulcer, malignancy must be ruled out. If symptoms persist despite adequate treatment, further investigation is 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 significantly reduced bioavailability (see section "Interaction with other medicinal products and other forms of interaction"). Vitamin B12 absorption. Pantoprazole may reduce vitamin B12 (cyanocobalamin) absorption due to hypo- or achlorhydria. This should be considered in patients with low body weight or risk factors for reduced vitamin B12 absorption during long-term treatment, or in the presence of relevant clinical symptoms. Long-term treatment. Patients on long-term treatment, especially longer than 1 year, should be under regular medical supervision. Gastrointestinal infections caused by bacteria. Treatment with Espa-prazol® slightly increases the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile. Hypomagnesemia. Rare cases of severe hypomagnesemia have been observed in patients receiving PPIs, including pantoprazole, for at least 3 months, mostly after 1 year. Serious clinical manifestations of hypomagnesemia, which may develop insidiously, include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia (see section "Adverse reactions"). In cases of hypomagnesemia (and associated hypocalcemia and/or hypokalemia), patient condition usually improved after magnesium replacement therapy and discontinuation of PPI. In patients requiring long-term therapy and in patients taking PPIs concomitantly with digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), magnesium levels should be measured before starting PPI therapy and periodically during treatment. Bone fractures. Long-term (more than 1 year), high-dose PPI treatment moderately increases the risk of hip, wrist, and spine fractures, primarily in elderly patients or those with other risk factors. Observational studies indicate that PPI use increases the overall fracture risk by 10–40%. Some of these may be attributable to other risk factors. Patients at risk of osteoporosis should be treated according to current clinical guidelines and should consume adequate vitamin D and calcium. Serious skin reactions. Serious skin reactions associated with pantoprazole use, which may be life-threatening or fatal, have been reported, including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). The frequency of these reactions is unknown (see section "Adverse reactions"). Patients should be informed of signs and symptoms and closely monitored. If symptoms suggestive of these reactions occur, pantoprazole should be discontinued immediately and alternative therapy considered. Subacute cutaneous lupus erythematosus. Use of proton pump inhibitors has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions occur, especially in sun-exposed areas, accompanied by arthralgia, the patient should seek immediate medical attention, and discontinuation of Espa-prazol® should be considered. Previous PPI therapy with subacute cutaneous lupus erythematosus increases the risk of recurrence with other PPIs. Effect on laboratory test results. Elevated chromogranin A (CgA) levels may affect diagnostic test results for neuroendocrine tumors. To avoid this effect, Espa-prazol® treatment should be temporarily discontinued at least 5 days before CgA level assessment (see section "Pharmacodynamics"). If CgA and gastrin levels do not return to normal after initial measurement, repeat measurements should be performed 14 days after discontinuation of PPI treatment. Sodium. The medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially sodium-free. Use during pregnancy or breastfeeding. Pregnancy. Available data on use of Espa-prazol® in pregnant women (approximately 300–1000 pregnancy outcomes) indicate no embryonal or fetal/neonatal toxicity. Reproductive toxicity was observed in animal studies. As a precautionary measure, use of Espa-prazol® in pregnant women should be avoided. Breastfeeding. Animal studies showed excretion of pantoprazole in milk. Insufficient data are available on excretion of pantoprazole in human breast milk, although such excretion has been reported. Risk to newborns/infants cannot be excluded. The decision to discontinue breastfeeding or discontinue/abstain from Espa-prazol® treatment should be made considering the benefits of breastfeeding for the child and the benefits of Espa-prazol® treatment 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 the ability to drive or operate machinery. Possible adverse reactions such as dizziness and visual disturbances should be considered (see section "Adverse reactions"). In such cases, driving or operating machinery should be avoided. Method of administration and dosage. Enteric-coated Espa-prazol® tablets should be taken whole, 1 hour before meals, without chewing or crushing, with water. Adults and children aged 12 years and older. Treatment of gastroesophageal reflux disease (GERD) with esophagitis. The recommended dose is 1 tablet of Espa-prazol® 40 mg once daily. In individual cases, the dose may be doubled (2 tablets of Espa-prazol® 40 mg daily), especially if no effect is observed with other GERD treatments. Treatment of GERD usually requires 4 weeks. If this is insufficient, healing may be expected within the next 4 weeks. Adults. Helicobacter pylori eradication in combination with two antibiotics. In adult patients with gastric or duodenal ulcers and a positive H. pylori test, eradication of the organism should be achieved with combination therapy. Local data on bacterial resistance and current guidelines for appropriate antibiotic use should be considered. Depending on sensitivity, the following treatment regimens may be prescribed for H. pylori eradication in adults: a) 1 tablet of Espa-prazol® 40 mg twice daily + 1000 mg amoxicillin twice daily + 500 mg clarithromycin twice daily; b) 1 tablet of Espa-prazol® 40 mg twice daily + 400–500 mg metronidazole (or 500 mg tinidazole) twice daily + 250–500 mg clarithromycin twice daily; c) 1 tablet of Espa-prazol® 40 mg twice daily + 1000 mg amoxicillin twice daily + 400–500 mg metronidazole (or 500 mg tinidazole) twice daily. For combination therapy for H. pylori eradication, the second Espa-prazol® 40 mg tablet should be taken in the evening, 1 hour before meals. Treatment duration is 7 days and may be extended for another 7 days. Total treatment duration should not exceed two weeks. If further pantoprazole treatment is indicated for 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, Espa-prazol® 40 mg should be used for monotherapy at the dosage specified below. Treatment of gastric ulcer. 1 tablet of Espa-prazol® 40 mg daily. In individual cases, the dose may be doubled (2 tablets of Espa-prazol® 40 mg daily), especially if no effect is observed with other treatments. Treatment of gastric ulcer usually requires 4 weeks. If this is insufficient, ulcer healing may be expected within the next 4 weeks. Treatment of duodenal ulcer. 1 tablet of Espa-prazol® 40 mg daily. In individual cases, the dose may be doubled (2 tablets of Espa-prazol® 40 mg daily), especially if no effect is observed with other treatments. Treatment of duodenal ulcer usually requires 2 weeks. If this is insufficient, ulcer healing may be expected within the next 2 weeks. Treatment of Zollinger-Ellison syndrome and other hypersecretory conditions. For long-term treatment of Zollinger-Ellison syndrome and other hypersecretory conditions, the initial daily dose is 80 mg (2 tablets of Espa-prazol® 40 mg). If necessary, the dose may then be titrated up or down based on gastric acid measurements. Doses exceeding 80 mg daily should be divided into two doses. Temporary dose increases above 160 mg pantoprazole may be possible, but duration of use should be limited to the period required for adequate acid control. Treatment duration for Zollinger-Ellison syndrome and other hypersecretory conditions is not limited and depends on clinical necessity. Hepatic impairment. Patients with severe hepatic impairment should not exceed a dose of 20 mg (1 tablet of Espa-prazol® 20 mg) daily. Espa-prazol® should not be used for H. pylori eradication in combination therapy in patients with moderate to severe hepatic impairment, as there are no data on efficacy and safety in this patient group. Renal impairment. Patients with renal impairment do not require dose adjustment. Espa-prazol® should not be used for H. pylori eradication in combination therapy in patients with renal impairment, as there are no data on efficacy and safety in this patient group. Elderly patients do not require dose adjustment. Children. Espa-prazol® 40 mg is indicated for treatment of GERD with esophagitis in children aged 12 years and older. The product is not recommended for children under 12 years due to limited safety and efficacy data in this age group. 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 readily dialyzable. In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy should be administered. No specific antidote is available. Adverse reactions. Adverse reactions may occur in approximately 5% of patients. The most common adverse reactions are diarrhea and headache (occurring in about 1% of patients). Adverse effects are classified by frequency 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), unknown (frequency cannot be estimated from available data). For all adverse reactions reported during the post-marketing period, frequency cannot be determined and is therefore listed as "unknown". Within each frequency category, adverse reactions are listed in order of decreasing severity. 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. Unknown: hyponatremia, hypomagnesemia (see section "Special warnings and precautions for use"), hypocalcemia1, hypokalemia. Psychiatric disorders. Uncommon: sleep disorders. Rare: depression (including exacerbation). Very rare: disorientation (including exacerbation). Unknown: hallucinations, confusion (especially in patients predisposed to such disorders, and exacerbation of pre-existing symptoms). Nervous system disorders. Uncommon: headache, dizziness. Rare: taste disturbances. Unknown: paresthesia. 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. Unknown: microscopic colitis. Hepatobiliary disorders. Uncommon: increased liver enzymes (transaminases, γ-glutamyl transferase). Rare: increased bilirubin levels. Unknown: hepatocellular injury, jaundice, hepatocellular failure. Skin and subcutaneous tissue disorders. Uncommon: skin rashes, exanthema, pruritus. Rare: urticaria, angioedema. Unknown: Stevens-Johnson syndrome, Lyell syndrome (toxic epidermal necrolysis), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special warnings and precautions for use"). Musculoskeletal and connective tissue disorders. Uncommon: fractures of the hip, wrist, spine (see section "Special warnings and precautions for use"). Rare: arthralgia, myalgia. Unknown: muscle spasms2. Renal and urinary disorders. Unknown: interstitial 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 warnings and precautions for use"). 2 Muscle spasms as a result of electrolyte imbalance. Reporting suspected adverse reactions. Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system (https://aisf.dec.gov.ua). Shelf life. 60 months for blisters made of aluminum foil on both sides. 30 months for blisters made of aluminum foil on one side and PVC/PE/PVdC film on the other. Storage conditions. Store in original packaging at temperatures not exceeding 25 °C. Keep out of reach of children! Packaging. 14 tablets in a blister (aluminum foil on both sides or aluminum foil on one side and PVC/PE/PVdC film on the other), 1 or 2 blisters per cardboard box. Prescription status. Prescription only. Manufacturer. Advanz Pharma GmbH, Germany. Manufacturer's address and place of business. Wallenroder Strasse 12–14, 13435, Berlin, Germany. |
