Pantoprazole-teva

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PANTOPRAZOLE-TEVA (PANTOPRAZOLE-TEVA)

Composition:

Active substance: pantoprazole:

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

Excipients: sodium hydrogen phosphate, mannite (E 421), microcrystalline cellulose, sodium croscarmellose, magnesium stearate, hypromellose, triethyl citrate, sodium starch glycolate (type A), methacrylic acid–ethyl acrylate copolymer (1:1), iron oxide yellow (E 172).

Pharmaceutical form. Gastro-resistant tablets.

Main physicochemical characteristics: yellow, oval, biconvex and smooth tablets, sized 11.6 mm × 6 mm.

Pharmacotherapeutic group. Drugs for treatment of acid-related disorders. Drugs for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. Pantoprazole. ATC code A02BC02.

Pharmacological properties.

Pharmacodynamics.

Pantoprazole is a substituted benzimidazole that inhibits gastric secretion of hydrochloric acid by specifically blocking the proton pumps of parietal cells. Pantoprazole is transformed into its active form in the acidic environment of parietal cells, where it inhibits the enzyme H+/K+-ATPase, thus blocking the final step of gastric acid production. Inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. In most patients, symptoms resolve within 2 weeks. As with other proton pump inhibitors (PPIs) and H2-receptor antagonists, pantoprazole reduces gastric acidity and thereby increases gastrin secretion proportionally to the reduction in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds the enzyme distal to cellular receptors, it can inhibit hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect after oral and intravenous administration is equivalent.

Administration of pantoprazole increases fasting gastrin levels. With short-term use, gastrin levels usually do not exceed the upper limit of normal. With long-term treatment, gastrin levels typically double. However, marked elevation occurs only in isolated cases. As a consequence, mild or moderate increase in specific enterochromaffin-like (ECL) cells in the stomach (ranging from simple to adenomatoid hyperplasia) may occasionally be observed during prolonged therapy. However, according to studies conducted to date, no development of precursor cells of neuroendocrine tumors (atypical hyperplasia) or gastric neuroendocrine tumors has been observed in humans, although such findings were reported in animal studies.

Based on results from animal studies, the influence of long-term (more than 1 year) pantoprazole treatment on thyroid endocrine parameters cannot be completely excluded.

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. In addition, due to decreased gastric acidity, chromogranin A (CgA) levels rise. Elevated CgA levels may interfere with diagnostic tests 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, which may be falsely elevated after PPI therapy, to return to the normal range.

Pharmacokinetics.

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

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

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

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

The majority of pantoprazole metabolites are excreted in urine (approximately 80%), with the remainder eliminated in feces. The main metabolite in both plasma and urine is desmethylpantoprazole sulfate conjugate. The elimination half-life of the main metabolite (approximately 1.5 hours) is only slightly longer than that of pantoprazole.

Special patient populations.

Poor metabolizers. Approximately 3% of Europeans lack functional CYP2C19 enzyme and are termed poor metabolizers. In these individuals, pantoprazole metabolism is likely primarily catalyzed by CYP3A4. After a single 40 mg dose, mean AUC was approximately 6 times higher in poor metabolizers compared to individuals with functional CYP2C19 (extensive metabolizers). Mean peak plasma concentration increased by approximately 60%. These findings do not affect pantoprazole dosing recommendations.

Renal impairment. Dose reduction is not recommended when pantoprazole is administered to patients with renal impairment, including those on dialysis. As in healthy volunteers, the elimination half-life of pantoprazole remains short. Only very small amounts of pantoprazole are dialyzed. Although the main metabolite has a moderately prolonged half-life (2–3 hours), elimination is still rapid, and no accumulation occurs.

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

Elderly patients. A slight increase in AUC and Cmax in elderly volunteers compared to younger volunteers has no clinical significance.

Pediatric patients. After a single oral dose of 20 mg or 40 mg pantoprazole, AUC and Cmax 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 mg/kg or 1.6 mg/kg to children aged 2 to 16 years, no significant relationship between pantoprazole clearance and age or body weight was observed. 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 erosive esophagitis.

Adults only.

• 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 pantoprazole, benzimidazole derivatives, or to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Medicinal products with pH-dependent absorption pharmacokinetics. Due to profound and long-lasting inhibition of gastric acid secretion, pantoprazole may interfere with the absorption of drugs for which gastric pH is an important factor in their oral bioavailability (e.g., certain azole 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 an acidic gastric pH, 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 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). Co-administration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon, or the international normalized ratio (INR). However, there have been reports of increased INR and prolonged prothrombin time in patients receiving PPIs concomitantly with warfarin or phenprocoumon. Elevated INR and prolonged prothrombin time may lead to serious or even fatal bleeding. When these drugs are used concomitantly, INR and prothombin time should be monitored.

Methotrexate. There have been reports that concomitant administration of high doses of methotrexate (e.g., 300 mg) and PPIs increases methotrexate levels in some patients. Patients receiving high-dose methotrexate, for example, in cancer or psoriasis treatment, 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 other pathways, including oxidation by CYP3A4. Interaction studies with drugs that are also metabolized via these pathways—such as carbamazepine, diazepam, glyburide (glibenclamide), nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—have not shown clinically significant interactions. However, interactions between pantoprazole and other drugs metabolized by the same enzyme system cannot be ruled out.

Results from several interaction studies indicate that pantoprazole does not affect the metabolism of active substances metabolized by CYP1A2 (e.g., caffeine, theophylline), CYP2C9 (e.g., piroxicam, diclofenac, naproxen), CYP2D6 (e.g., metoprolol), or CYP2E1 (e.g., ethanol). Pantoprazole does not affect P-glycoprotein, which is involved in digoxin absorption.

No interaction has been observed with concomitantly administered antacids.

Studies investigating the interaction between pantoprazole and certain concomitantly administered antibiotics (clarithromycin, metronidazole, amoxicillin) have not revealed any clinically significant interactions.

Medicinal products that inhibit or induce CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, may increase systemic exposure to pantoprazole. Consideration should be given to reducing the dose in patients receiving long-term, high-dose pantoprazole therapy and in 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 by these enzyme systems.

Special precautions for use

Hepatic impairment. Patients with severe hepatic impairment should have regular monitoring of liver enzymes, especially during long-term treatment. If liver enzymes increase, the drug should be discontinued (see section "Dosage and administration").

Combination therapy. When using combination therapy, instructions provided in the respective product information leaflets for the medicinal products should be followed.

Gastric malignancies. Symptomatic response to pantoprazole may mask symptoms of gastric malignancies and delay their diagnosis. In the presence of alarm symptoms (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena), as well as in suspected or confirmed gastric ulcer, malignancy must be excluded. If symptoms persist despite adequate treatment, further investigations are required.

Concomitant use with HIV protease inhibitors. Concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir), whose absorption is dependent on an acidic 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. In patients with Zollinger–Ellison syndrome and other pathological hypersecretory conditions requiring long-term treatment, pantoprazole, like all drugs that inhibit gastric acid production, may reduce absorption of vitamin B12 (cyanocobalamin) due to the development of hypochlorhydria or achlorhydria. This should be considered in patients with low body stores or risk factors for reduced vitamin B12 absorption during prolonged therapy, or in the presence of relevant clinical symptoms.

Long-term treatment. Patients undergoing long-term treatment, particularly exceeding 1 year, should be under regular medical supervision.

Gastrointestinal infections caused by bacteria. Pantoprazole, like other proton pump inhibitors (PPIs), may increase the number of bacteria normally present in the upper gastrointestinal tract. Treatment with pantoprazole may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile.

Hypomagnesemia. Cases of severe hypomagnesemia have been reported in patients treated with PPIs such as pantoprazole for at least 3 months, and mostly after a year of treatment. Serious clinical manifestations of hypomagnesemia, which may initially be subtle, include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. In cases of hypomagnesemia (and associated hypocalcemia and/or hypokalemia), patients' conditions generally improved after magnesium replacement therapy and discontinuation of PPI treatment. Patients requiring long-term therapy, or those taking PPIs concomitantly with digoxin or medications that may cause hypomagnesemia (e.g. diuretics), should have serum magnesium levels measured before initiating PPI treatment and periodically during treatment.

Bone fractures. Long-term (more than 1 year) high-dose PPI treatment may moderately increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other risk factors. Observational studies suggest that PPI use may increase the overall risk of fractures 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.

Subacute cutaneous lupus erythematosus (SCLE). PPI use 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, patients should seek immediate medical advice, and discontinuation of pantoprazole should be considered. Previous occurrence of SCLE during prior PPI therapy may increase the risk of recurrence with other PPIs.

Effect on laboratory test results. Elevated chromogranin A (CgA) levels may interfere with diagnostic tests for neuroendocrine tumors. To avoid this interference, pantoprazole treatment should be temporarily discontinued at least 5 days before measuring CgA levels. If CgA and gastrin levels do not return to the reference range after initial measurement, repeat measurements should be performed 14 days after stopping PPI treatment.

This medicinal product contains less than 1 mmol of sodium (23 mg) per gastro-resistant tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy. Data from a moderate number of pregnant women (from 300 to 1000 pregnancy outcomes) indicate no malformations or fetotoxic/neonatal toxicity associated with pantoprazole. Animal studies have shown reproductive toxicity. As a precautionary measure, pantoprazole should be avoided during pregnancy.

Breastfeeding. Animal studies have shown excretion of pantoprazole into breast milk. Data on excretion of pantoprazole into human breast milk are limited, although excretion into human breast milk has been reported. Risk to newborns/infants cannot be excluded. The decision whether to continue/discontinue breastfeeding or to continue/discontinue pantoprazole therapy should be made taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility. Animal studies have shown no effects on fertility after administration of pantoprazole.

Ability to affect reaction speed when driving or operating machinery.

Pantoprazole has no effect or has a negligible effect on the ability to drive or operate machinery. Adverse reactions such as dizziness and visual disturbances may occur. In such cases, patients should refrain from driving or operating machinery.

Method of Administration and Dosage.

The medicinal product Pantoprazole-Teva, gastro-resistant tablets, should be taken whole, 1 hour before a meal. Do not chew or crush. Swallow with sufficient amount of water.

Recommended Dosage.

Adults and children aged 12 years and older.

Treatment of reflux esophagitis.

The recommended dose is 1 tablet of Pantoprazole-Teva 40 mg once daily. In individual cases, the dose may be doubled (2 tablets of Pantoprazole-Teva 40 mg daily), 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 healing is not achieved, it may be expected during the following 4 weeks.

Adults.

Eradiсation of H. pylori in combination with two antibiotics.

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

a) 1 tablet of Pantoprazole-Teva 40 mg twice daily

• 1000 mg amoxicillin twice daily

• 500 mg clarithromycin twice daily;

b) 1 tablet of Pantoprazole-Teva 40 mg twice daily

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

• 250–500 mg clarithromycin twice daily;

c) 1 tablet of Pantoprazole-Teva 40 mg twice daily

• 1000 mg amoxicillin twice daily

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

When using combination therapy for H. pylori eradication, the second tablet of Pantoprazole-Teva 40 mg should be taken in the evening, 1 hour before a meal. The treatment duration is 7 days and may be extended for another 7 days, with a total treatment duration not exceeding 2 weeks. If further treatment with pantoprazole is indicated to ensure ulcer healing, dosage 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 result, Pantoprazole-Teva 40 mg may be used as monotherapy at the dosage specified below.

Treatment of gastric ulcer.

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

Treatment of gastric ulcer usually requires 4 weeks. If healing is not achieved, it may be expected during the following 4 weeks.

Treatment of duodenal ulcer.

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

Treatment of duodenal ulcer usually requires 2 weeks. If healing is not achieved, it 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 hypersecretory conditions, the initial daily dose is 80 mg (2 tablets of Pantoprazole-Teva 40 mg). If necessary, the dose may be titrated up or down depending on gastric acid secretion parameters. Doses exceeding 80 mg daily should be divided into two doses. Temporary dose increases above 160 mg of pantoprazole may be considered, but the duration of such treatment should be limited to the period required for adequate acid control.

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

Special patient populations.

Patients with hepatic impairment. In patients with severe hepatic impairment, the daily dose should not exceed 20 mg (1 tablet of 20 mg pantoprazole). Pantoprazole-Teva 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 the efficacy and safety of such use in this patient group.

Patients with renal impairment. Dose adjustment is not required in patients with renal impairment. Pantoprazole-Teva 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 in this patient group.

Elderly patients do not require dose adjustment.

Children. The medicinal product is not recommended for use in children under 12 years of age, as data on safety and efficacy in this age group are limited.

Overdose.

Symptoms of overdose are unknown. Doses up to 240 mg administered intravenously over 2 minutes were well tolerated. Since pantoprazole is highly protein-bound, it is not readily removed by dialysis. In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy should be administered. Specific antidotes are not available.

Adverse reactions.

Adverse reactions may be expected in approximately 5% of patients. The most common adverse reactions — diarrhea and headache — occur in 1% of patients.

Adverse reactions are classified by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data). For all adverse reactions reported during the post-marketing period, frequency cannot be determined; therefore, they are listed as having a frequency of "frequency not known". 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. Frequency not known: hyponatremia, hypomagnesemia (see section "Special precautions for use"), hypocalcemia (may be associated with hypomagnesemia), hypokalemia (may be associated with hypomagnesemia).

Psychiatric disorders. Uncommon: sleep disorders. Rare: depression (including exacerbation). Very rare: confusion (including exacerbation). Frequency 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. Frequency not known: paresthesia.

Eye disorders. Rare: visual disturbances/blurred vision.

Gastrointestinal disorders. Common: fundic gland polyps (benign). Uncommon: diarrhea, nausea, vomiting, abdominal distension, constipation, dry mouth, abdominal pain and discomfort. Frequency not known: microscopic colitis.

Hepatobiliary disorders. Uncommon: increased 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. Frequency not known: Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special precautions for use"), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders. Uncommon: fractures of femur, wrist, spine (see section "Special precautions for use"). Rare: arthralgia, myalgia. Frequency not known: muscle spasms, as a consequence of electrolyte disturbances.

Renal and urinary disorders. Frequency not known: interstitial nephritis (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.

Reporting of suspected adverse reactions. All suspected adverse reactions and lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua/.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 30 °C. Keep out of reach of children.

Packaging. 7 tablets per blister, 2 or 4 blisters per carton; 10 tablets per blister, 3 blisters per carton; 14 tablets per blister, 1 or 2 blisters per carton; 15 tablets per blister, 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Teva Pharma S.L.U.

Manufacturer's location and address of place of business.

Polígono Industrial Malpica c/C nº 4, 50016, Zaragoza, Spain.