INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PELTA® (PELTA)

Composition:

Active substance: pantoprazole;

One gastro-resistant tablet contains 45.1 mg of pantoprazole sodium sesquihydrate, equivalent to 40 mg of pantoprazole;

Excipients: mannite (E 421), crospovidone, anhydrous sodium carbonate, hydroxypropylcellulose, calcium stearate, hypromellose, titanium dioxide (E 171), yellow iron oxide (E 172), propylene glycol, methacrylate copolymer dispersion, triethyl citrate, talc.

Pharmaceutical form. Gastro-resistant tablets.

Main physicochemical properties: oval, biconvex tablets coated with a yellow film, smooth on both sides.

Pharmacotherapeutic group.

Drugs for treatment of acid-related disorders. Proton pump inhibitors. Pantoprazole. ATC code A02BC02.

Pharmacological Properties

Pharmacodynamics. Mechanism of action. Pantoprazole is a substituted benzimidazole that inhibits gastric hydrochloric acid secretion by specifically blocking the H+/K+-ATPase proton pumps of 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 acid production. Inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, symptoms resolve within 2 weeks. The use of pantoprazole, as with other proton pump inhibitors (PPIs) and H2-receptor antagonists, reduces gastric acidity and consequently increases gastrin secretion proportionally to the reduction in acidity. This increase in gastrin secretion is reversible. Since pantoprazole binds to 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 both oral and intravenous administration.

Pantoprazole increases fasting gastrin levels. With short-term use, levels typically do not exceed the upper normal limit. With long-term treatment, gastrin levels usually increase approximately twofold. Marked elevation occurs only in isolated cases. As a result, mild or moderate increase in gastric enterochromaffin-like (ECL) cells (similar to adenomatoid hyperplasia) may occasionally be observed during prolonged therapy. However, to date, studies have not shown the development of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors in humans, although such findings were observed in animal studies.

Based on animal studies, the influence of long-term (more than one year) pantoprazole treatment on thyroid endocrine parameters cannot be completely ruled out.

During treatment with acid-suppressing agents, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels rise. Elevated CgA levels may interfere with diagnostic testing for neuroendocrine tumors. Available published data indicate that PPI treatment should be discontinued for a period of 5 days to 2 weeks prior to CgA measurement. This allows CgA levels, which may be falsely elevated after PPI treatment, 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, Cmax of approximately 2–3 µg/mL is reached within 2.5 hours after administration; plasma concentrations remain stable after 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 for both oral and intravenous administration. Absolute bioavailability of pantoprazole in tablet form is approximately 77%. Concomitant food intake does not affect the area under the concentration-time curve (AUC) or Cmax, and therefore does not affect bioavailability. Food intake only increases the variability of the lag time.

Distribution. Plasma protein binding of pantoprazole 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 effect (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 groups

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

Renal impairment. No dose adjustment is recommended for patients with impaired renal function (including dialysis patients). As in healthy volunteers, the elimination half-life of pantoprazole remains 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, and thus accumulation does not occur.

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 compared to healthy volunteers, Cmax increases only slightly (by 1.5 times).

Elderly patients. The slight increase in AUC and Cmax observed in elderly volunteers compared to younger volunteers is not considered clinically significant.

Children. 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 a single intravenous dose of 0.8 mg/kg or 1.6 mg/kg 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 were comparable to those in adults.

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, or to any component 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 gastric acid secretion, pantoprazole may affect the absorption of drugs for which gastric pH is an important factor in their bioavailability (e.g., certain antifungal agents such as ketoconazole, itraconazole, posaconazole, or other drugs such as erlotinib).

HIV protease inhibitors. Concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir), whose absorption is pH-dependent, is not recommended due to a significant reduction in their bioavailability (see section "Special warnings and precautions for use").

If concomitant use of HIV protease inhibitors with 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). Concomitant administration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon, or the international normalized ratio (INR). However, increased INR and prolonged prothrombin time have been reported in patients receiving concomitant PPIs and warfarin or phenprocoumon. Elevated INR and prolonged prothrombin time may lead to pathological bleeding and even fatal outcomes. Therefore, monitoring of INR and prothrombin time is necessary when these drugs are used concomitantly.

Methotrexate. It has been observed that concomitant use 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 that are also metabolized through these pathways, such as carbamazepine, diazepam, glyburide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol, have not revealed clinically significant interactions.

Interaction between pantoprazole and other drugs 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 (e.g., caffeine, theophylline), CYP2C9 (e.g., piroxicam, diclofenac, naproxen), CYP2D6 (e.g., metoprolol), CYP2E1 (e.g., ethanol), and does not affect P-glycoprotein associated with 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 not shown clinically significant interactions.

Medicinal products that inhibit or induce CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, may increase the systemic exposure to pantoprazole. Consideration should be given to reducing the dose in patients receiving long-term, high-dose pantoprazole therapy and in patients with impaired liver function. Enzyme inducers affecting CYP2C19 and CYP3A4, such as rifampicin and St. John's wort (Hypericum perforatum), may reduce plasma concentrations of PPIs metabolized by these enzyme systems.

Special precautions for use.

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

Combination therapy. When using combination therapy, instructions for medical use of the corresponding 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 weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena), or suspicion or presence of gastric ulcer, malignancy must be excluded.

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

Vitamin B12 absorption. In patients with Zollinger-Ellison syndrome and other hypersecretory conditions requiring long-term treatment, pantoprazole, like all drugs that inhibit gastric acid secretion, may reduce absorption of vitamin B12 (cyanocobalamin) due to the development of hypochlorhydria or achlorhydria. This should be considered in cases of weight loss, presence of risk factors for reduced vitamin B12 absorption during long-term treatment, or presence of relevant clinical symptoms.

Long-term treatment. During prolonged treatment, especially longer than one year, patients should be under regular medical supervision.

Gastrointestinal infections caused by bacteria. Treatment with Pelta® 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 observed in patients treated with PPIs, such as pantoprazole, for at least three months, and mostly within a year. Serious clinical manifestations of hypomagnesemia, such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, may occur and develop insidiously. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia (see section "Adverse reactions"). In cases of hypomagnesemia, the condition of patients usually improved after replacement therapy with magnesium supplements and discontinuation of PPI treatment.

Patients requiring long-term therapy, or patients receiving PPIs concomitantly with digoxin or medications that may cause hypomagnesemia (e.g., diuretics), should have their magnesium levels determined before initiating PPI treatment and periodically during treatment.

Bone fractures. Prolonged treatment (more than one year) with high doses of PPIs 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 fracture risk by 10–40%. Some of these may be attributable to other risk factors. Patients at risk of developing osteoporosis should receive treatment according to current clinical guidelines and ensure adequate intake of vitamin D and calcium.

Subacute cutaneous lupus erythematosus. The use of PPIs has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions develop, particularly in sun-exposed areas, and are accompanied by arthralgia, the patient should seek immediate medical advice, and discontinuation of Pelta® should be considered. Development of subacute cutaneous lupus erythematosus in patients during prior PPI therapy may increase the risk of recurrence when using other PPIs.

Effect on laboratory test results

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

Use during pregnancy or breastfeeding.

Pregnancy. Available data on the use of pantoprazole in pregnant women (approximately 300–1000 reports on pregnancy outcomes) indicate no embryonal or fetoneonatal toxicity of the drug. Reproductive toxicity was observed in animal studies. As a precautionary measure, use of Pelta® in pregnant women should be avoided.

Breastfeeding. Animal studies have shown excretion of pantoprazole into breast milk. There are insufficient data on excretion of pantoprazole into human breast milk, but such excretion has been reported. Risk to newborns/infants cannot be excluded. The decision to discontinue breastfeeding or to discontinue/abstain from treatment with Pelta® should be made taking into account the benefit of breastfeeding for the child and the benefit of treatment with Pelta® 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 reaction speed when driving or operating machinery. The possible development of adverse reactions such as dizziness and visual disturbances should be taken into account (see section "Adverse reactions"). In such cases, driving or operating machinery should be avoided.

Method of Administration and Dosage

The medicinal product Pelta®, enteric-coated tablets, should be taken whole, 1 hour before a meal. Do not chew or crush the tablets. Swallow with water.

Recommended Dosage

Adults and Children Aged 12 Years and Older

Treatment of Reflux Esophagitis

The recommended dose for children aged 12 years and older and adults is 1 tablet (40 mg) once daily. In individual cases, the dose may be doubled (2 tablets of Pelta® 40 mg per day), especially if there is no response to other treatments for reflux esophagitis. Treatment of reflux esophagitis usually requires 4 weeks. If this is insufficient, healing may be expected within the following 4 weeks.

Adults

Helicobacter pylori Eradication in Combination with Two Antibiotics

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

a) 1 tablet of Pelta® 40 mg twice daily

1000 mg amoxicillin twice daily
500 mg clarithromycin twice daily;

b) 1 tablet of Pelta® 40 mg twice daily

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

c) 1 tablet of Pelta® 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 dose of Pelta® 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 two weeks. If further treatment with pantoprazole is indicated to ensure ulcer healing, refer to the dosage recommendations for gastric and duodenal ulcers. If combination therapy is not indicated, e.g., in patients with a negative H. pylori test, monotherapy with Pelta® 40 mg should be administered at the dosage specified below.

Treatment of Gastric Ulcer

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

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

Treatment of Duodenal Ulcer

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

Treatment of duodenal ulcer usually requires 2 weeks. If this is insufficient, healing may be expected within 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 Pelta® 40 mg). If necessary, the dose may subsequently be titrated up or down based on gastric acid secretion parameters. Daily doses exceeding 80 mg should be divided into two administrations. Temporary dose increases above 160 mg of pantoprazole may be possible, but duration of use should be limited to the period required for adequate acid control.

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

Patients with Hepatic Impairment. In patients with severe hepatic impairment, the daily dose should not exceed 20 mg (1 tablet of Pelta® 20 mg). Pelta® 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 of such use in this patient population.

Patients with Renal Impairment. Dose adjustment is not required in patients with renal impairment. Pelta® 20 mg 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 of such use in this patient population.

Elderly Patients do not require dose adjustment.

Children.

Pelta® is indicated for children aged 12 years and older for the treatment of reflux esophagitis. The 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 extensively protein-bound, it is not readily removable by dialysis.

In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy should be administered. There are no specific antidotes or recommended specific treatments.

Adverse Reactions

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

Adverse reactions are classified by frequency of occurrence as follows: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), frequency not known (frequency 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 "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 warnings and precautions for use"), hypocalcemia¹, hypokalemia.

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, and exacerbation of these symptoms if pre-existing).

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 (benign).

Uncommon: diarrhea, nausea, vomiting, bloating, 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, drug reaction with eosinophilia and systemic symptoms (DRESS), subacute cutaneous lupus erythematosus (see section "Special warnings and precautions for use").

Musculoskeletal and connective tissue disorders

Uncommon: fractures of the femur, wrist, spine (see section "Special warnings and precautions for use").

Rare: arthralgia, myalgia.

Frequency not known: muscle spasms².

Renal and urinary disorders

Frequency not known: interstitial 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 occurring simultaneously with hypomagnesemia.

² Muscle spasms as a consequence of electrolyte imbalance.

Reporting suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Packaging. 10 tablets per blister, 3 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

Torrent Pharmaceuticals Ltd.

Manufacturer's address.

Indrad Plant, Near Indrad Village, Taluka Kadi, District Mehsana, Gujarat 382721, India.

Marketing Authorization Holder. JSC "Farmak".

Address of Marketing Authorization Holder. 63, Kyrylivska St., Kyiv, 04080, Ukraine.