INSTRUCTIONS FOR MEDICINAL USE OF THE MEDICINAL PRODUCT PELTA® (PELTA)

Composition:

Active substance: pantoprazole;

One gastro-resistant tablet contains 22.55 mg of pantoprazole sodium sesquihydrate, equivalent to 20 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 the 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 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. 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 equivalent following oral and intravenous administration.

Pantoprazole increases fasting gastrin levels. With short-term use, gastrin levels usually remain within the upper normal range. With long-term treatment, gastrin levels typically double; excessive increases occur only in isolated cases. As a consequence, prolonged therapy may occasionally lead to mild or moderate increases in gastric enterochromaffin-like (ECL) cells (similar to adenomatoid hyperplasia). However, according to studies conducted to date, the development of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors, as observed in animal studies, has not been observed in humans.

Based on animal study results, a potential effect of long-term (more than one year) pantoprazole treatment on thyroid gland 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 decreased gastric acidity, chromogranin A (CgA) levels rise. Elevated CgA levels may interfere with diagnostic testing for neuroendocrine tumors. Published data indicate that PPI treatment should be discontinued for a period of 5 days to 2 weeks prior to 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; its maximum plasma concentration (C_max) is achieved after a single oral dose of 20 mg. On average, C_max is reached within 2–2.5 hours after administration at approximately 1–1.5 µg/mL; concentrations remain stable with repeated dosing.

Pharmacokinetic properties do not change after single or repeated administration. Within the dose range of 10 mg to 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 the area under the concentration-time curve (AUC) or C_max, 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%; volume of distribution is about 0.15 L/kg.

Metabolism. The substance is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation via CYP2C19, followed by sulfate conjugation. 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%), the remainder in feces. The main metabolite in both plasma and urine is desmethylpantoprazole sulfate conjugate. The half-life of the main metabolite (approximately 1.5 hours) is slightly longer than that of pantoprazole.

Special patient groups

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

Renal impairment. No dose adjustment is recommended for pantoprazole in patients with renal impairment, including those on dialysis. As in healthy individuals, 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 remains sufficiently rapid to prevent accumulation.

Hepatic impairment. Although in patients with liver cirrhosis (Child-Pugh classes A and B), the elimination half-life increases to 3–6 hours and AUC increases 3–5 times compared to healthy volunteers, C_max increases only slightly—by 1.3 times.

Elderly patients. A slight increase in AUC and C_max in elderly volunteers compared to younger volunteers is not clinically significant.

Pediatric patients. Following single oral doses of 20 mg or 40 mg pantoprazole, AUC and C_max in children aged 5 to 16 years were within the range observed in adults. After single intravenous pantoprazole doses 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 corresponded to data obtained in adult studies.

Clinical characteristics.

Indications.

Adults and children aged 12 years and older:

symptomatic treatment of gastroesophageal reflux disease (GERD);
long-term treatment and prevention of relapses of reflux esophagitis.

Adults:

prevention of gastric and duodenal ulcer formation associated with the use of non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) in high-risk patients who require long-term NSAID therapy.

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 hydrochloric acid secretion, pantoprazole may affect the absorption of drugs for which gastric juice pH is an important factor for 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 depends on intragastric 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). Concomitant 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 concomitant PPIs and warfarin or phenprocoumon. Increased INR and prolonged prothrombin time may lead to the development of 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 administration of high doses of methotrexate (e.g., 300 mg) and PPIs increases methotrexate blood levels in some patients. Patients receiving high doses of methotrexate, such as those with cancer or psoriasis, should temporarily discontinue pantoprazole therapy.

Other interactions. Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19, as well as other metabolic pathways, including oxidation by the enzyme CYP3A4. Studies with drugs that are also metabolized via 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 via 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 been conducted. No clinically significant interactions between these drugs were observed.

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 via these enzyme systems.

Special precautions for use.

Hepatic function impairment. Patients with severe impairment of liver function should have 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 method of administration").

Concomitant use with NSAIDs. Long-term use of Pelta® 20 mg tablets for prevention of gastric and duodenal ulcers induced by NSAIDs should be limited in patients prone to frequent recurrences of gastric and duodenal ulcers.

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

Malignant gastric tumours. Symptomatic response to pantoprazole may mask symptoms of malignant gastric tumours and delay their diagnosis. In the presence of alarm symptoms (e.g. significant weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia, melena), or suspicion of or existing gastric ulcer, malignancy must be ruled out.

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

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 "Interaction with other medicinal products and other forms of interaction").

Vitamin B12 absorption. In patients with Zollinger-Ellison syndrome and other hypersecretory conditions requiring long-term treatment, pantoprazole, like all agents that inhibit gastric acid secretion, may reduce absorption of vitamin B12 (cyanocobalamin) due to the development of hypo- or achlorhydria. This should be considered in patients with weight loss or risk factors for reduced vitamin B12 absorption during long-term treatment, or in the 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 the medicinal product may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile.

Hypomagnesaemia. Cases of severe hypomagnesaemia have been reported in patients treated with PPIs, such as pantoprazole, for at least three months, in most cases after one year. Serious clinical manifestations of hypomagnesaemia, such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, may develop insidiously. Hypomagnesaemia may lead to hypocalcaemia and/or hypokalaemia (see section "Adverse reactions"). In cases of hypomagnesaemia, the condition of patients usually 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 hypomagnesaemia (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 moderately increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or in the presence of other risk factors. Observational studies suggest that PPI use may increase the overall fracture risk by 10–40%. Some of these fractures may be attributable to other risk factors. Patients at risk of developing 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 the medicinal product should be considered. Development of SCLE in patients during previous 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 tumours. To avoid such interference, treatment with Pelta® should be temporarily discontinued at least 5 days before assessing CgA levels (see section "Pharmacodynamics"). If CgA and gastrin levels do not return to 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 pregnancy outcomes reported) indicate no embryonal or fetoneonatal toxicity of pantoprazole. Reproductive toxicity was observed in animal studies. As a precautionary measure, use of Pelta® in pregnant women should be avoided.

Breastfeeding period. 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 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 has a negligible effect on reaction speed when driving or operating machinery. However, the possible development of 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

Pelta®, gastro-resistant tablets, should be taken whole, one hour before meals, without chewing or crushing, and with water.

Recommended Dosage

Adults and children aged 12 years and older

Symptomatic treatment of gastroesophageal reflux disease

The recommended dose is 20 mg (1 tablet) of Pelta® once daily. Symptoms of heartburn usually resolve within 2–4 weeks. If this period is insufficient, treatment may be continued for an additional 4 weeks. After symptom resolution, recurrence of symptoms can be managed on-demand by taking 20 mg (1 tablet) once daily as needed. Long-term therapy should be considered if adequate symptom control is not achieved with on-demand treatment.

Long-term treatment and prevention of relapses of reflux esophagitis

For long-term maintenance therapy, the recommended dose is 20 mg (1 tablet) of Pelta® once daily. During disease exacerbations, the dose may be increased to 40 mg daily. In such cases, administration of 40 mg Pelta® tablets is recommended. After resolution of the relapse, the dose can be reduced again to 20 mg once daily.

Adults

Prevention of gastric and duodenal ulcers induced by non-selective NSAIDs in high-risk patients requiring long-term NSAID therapy

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

Hepatic impairment. Patients with severe hepatic impairment should not exceed a daily dose of 20 mg (1 tablet).

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

Elderly patients do not require dose adjustment.

Children

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. Since pantoprazole is highly protein-bound, it is not readily dialyzable.

In case of overdose with clinical signs of intoxication, symptomatic and supportive treatment should be administered. There are no recommendations for specific antidotal therapy.

Adverse Reactions

Adverse reactions can be expected in approximately 5% of patients. The most common adverse reactions are 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 (≥ 1/10000 and < 1/1000), very rare (< 1/10000), frequency not known (frequency cannot be estimated from available data).

For all adverse reactions reported during the post-marketing period, it is not possible to determine frequency; 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 precautions"), hypocalcemia^1, hypokalemia.

Psychiatric disorders

Uncommon: sleep disorders.

Rare: depression (including exacerbation).

Very rare: disorientation (including exacerbation).

Frequency not known: hallucinations, confusion (particularly in patients predisposed to such disorders, and including 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, 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, Lyell's syndrome, erythema multiforme, photosensitivity, drug reaction with eosinophilia and systemic symptoms (DRESS), subacute cutaneous lupus erythematosus (see section "Special precautions").

Musculoskeletal and connective tissue disorders

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

Rare: arthralgia, myalgia.

Frequency not known: muscle spasms^2.

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.

^1 Hypocalcemia together with hypomagnesemia.

^2 Muscle spasms as a result of electrolyte imbalance.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and patients 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 the reach of children.

Packaging. 10 tablets in a blister pack, 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Torrent Pharmaceuticals Ltd.

Manufacturer's address and site of manufacturing.

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

Marketing Authorization Holder. JSC "Farmak".

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