INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PANTOZOL (PANTOZOL)

Composition:

Active substance: pantoprazole;

One tablet contains 45.1 mg of pantoprazole sodium sesquihydrate equivalent to 40 mg of pantoprazole;

Excipients: crospovidone, calcium stearate, Opadry II 85G68918 White (polyvinyl alcohol – partially hydrolyzed, titanium dioxide (E171), talc, macrogol/PEG, soy lecithin), sodium hydroxide, Opadry AcrylO Yellow 93O92052 (methacrylic acid copolymer type C, talc, titanium dioxide (E171), triethyl citrate, colloidal anhydrous silicon dioxide, sodium bicarbonate, iron oxide yellow (E172), sodium lauryl sulfate), simethicone emulsion (30%), mannitol (E421), anhydrous sodium carbonate, povidone.

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical characteristics: light yellow to yellow, round, biconvex, enteric-coated tablets.

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 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, thereby blocking the final step of gastric hydrochloric acid production. Inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, symptoms resolve within 2 weeks. As with other proton pump inhibitors and H₂-receptor antagonists, pantoprazole reduces gastric acidity and consequently increases gastrin secretion proportionally to the reduction in acidity. This 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.

With pantoprazole use, fasting gastrin levels increase. With short-term treatment, these levels usually do not exceed the upper limit of normal. With long-term treatment, gastrin levels typically double. Marked elevation occurs only in isolated cases. As a consequence, during prolonged therapy, mild or moderate increases in specific endocrine cells of the stomach (similar to adenomatoid hyperplasia) may occasionally be observed. However, according to studies conducted to date, the development of precursor cells of neuroendocrine tumors (atypical hyperplasia) or gastric neuroendocrine tumors has not been observed in humans.

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

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. Available published data indicate that proton pump inhibitor therapy 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 treatment, to return to the normal range.

Pharmacokinetics.

Absorption. Pantoprazole is rapidly absorbed, and maximum plasma concentrations (C_max) are achieved after a single oral dose of 40 mg. On average, C_max in serum reaches approximately 2–3 µg/mL within 2.5 hours after administration; concentrations remain stable with repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. In the dose range of 10 to 80 mg, pantoprazole pharmacokinetics 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 concentration-time curve (AUC) or C_max in serum, and thus does not affect bioavailability. Food intake only increases the variability of the latency period.

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

Biological transformation. Pantoprazole 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 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 a functional deficiency in CYP2C19 enzyme activity; these individuals are termed slow metabolizers. In such individuals, pantoprazole metabolism is likely primarily catalyzed by CYP3A4. After a single 40 mg dose, the mean AUC was approximately 6 times higher in slow metabolizers compared to individuals with functionally active CYP2C19 (fast metabolizers). The mean peak plasma concentration increased by approximately 60%. These findings do not affect pantoprazole dosing.

Renal impairment. No dose adjustment is recommended when prescribing pantoprazole to 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 removed by dialysis. Although the main metabolite has a moderately prolonged half-life (2–3 hours), elimination is still 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, C_max in serum increases only slightly—by 1.5 times compared to healthy volunteers.

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

Children. After a single oral dose of 20 or 40 mg pantoprazole, AUC and C_max in children aged 5 to 16 years were within the range observed in adults. After a single intravenous dose of pantoprazole at 0.8 or 1.6 mg/kg in children aged 2 to 16 years, no significant relationship was observed between pantoprazole clearance and 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).

Adults.

Eradication of Helicobacter pylori (H. pylori) in patients with H. pylori-associated gastric and duodenal ulcers, in combination with certain 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 whose absorption is pH-dependent. 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 (e.g., 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 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 or phenprocoumon or the INR (International Normalized Ratio). However, there have been reports of increased INR and prolonged prothrombin time in patients receiving PPIs and warfarin or phenprocoumon concurrently. Increased INR and prolonged prothrombin time may lead to serious bleeding or even death. Therefore, monitoring of INR and prothrombin time is required when these drugs are used concomitantly.

Methotrexate. There have been reports that concomitant administration of high-dose methotrexate (e.g., 300 mg) and proton pump inhibitors 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, with additional metabolic pathways including oxidation by 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 ruled out.

Results from multiple 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), or CYP2E1 (e.g., ethanol), and does not affect P-glycoprotein involved in digoxin absorption.

No interaction has been observed with concomitantly administered antacids.

Studies on the interaction between pantoprazole and 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.

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

Special precautions for use.

Hepatic impairment. Patients with severe 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 administration").

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

Gastric malignancies. Symptomatic response to pantoprazole may mask symptoms of gastric malignancies and delay their diagnosis. In the presence of alarm symptoms (significant weight loss, recurrent vomiting, dysphagia, hematemesis, anaemia, melena), or suspicion or presence of gastric ulcer, malignancy must be excluded.

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 depends on intragastric pH, is not recommended due to a significant reduction in their bioavailability (see section "Interaction with other medicinal products and other forms of interactions").

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 production, may reduce absorption of vitamin B12 (cyanocobalamin) due to the development of hypo- or achlorhydria. This should be considered in patients with low body weight, risk factors for reduced vitamin B12 absorption during long-term treatment, or presence of relevant clinical symptoms.

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

Gastrointestinal infections caused by bacteria. Treatment with pantoprazole 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 proton pump inhibitors (PPIs), such as pantoprazole, for at least three months, and in most cases, after one year. Serious clinical manifestations of hypomagnesaemia may occur and initially develop insidiously: fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. Hypomagnesaemia may lead to the development of hypocalcaemia and/or hypokalaemia (see section "Adverse reactions"). In most cases, patient condition improved after replacement therapy with magnesium supplements and discontinuation of PPI treatment.

Patients requiring long-term therapy, or those receiving PPIs concomitantly with digoxin or medications that may cause hypomagnesaemia (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 treatment with proton pump inhibitors may slightly increase the risk of fractures of the hip, wrist, and spine, particularly in elderly patients or those with other risk factors. Study data indicate that the use of proton pump inhibitors 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 consume adequate amounts of vitamin D and calcium.

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

Subacute cutaneous lupus erythematosus. The use of proton pump inhibitors 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 attention, and discontinuation of pantoprazole should be considered. Previous occurrence of subacute cutaneous lupus erythematosus during prior therapy with proton pump inhibitors may increase the risk of its recurrence with other proton pump inhibitors.

Effect on laboratory test results.

Elevated chromogranin A (CgA) levels may interfere with diagnostic testing for neuroendocrine tumours. To avoid this interference, pantoprazole treatment should be temporarily discontinued at least 5 days before assessment of 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 proton pump inhibitor therapy.

Use during pregnancy or breastfeeding.

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

Breastfeeding. Animal studies have shown excretion of pantoprazole into breast milk. There is limited 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 pantoprazole therapy should be based on the benefit of breastfeeding for the child and the benefit of pantoprazole therapy for the woman.

Fertility. Pantoprazole did not impair fertility in animal studies.

Ability to influence 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 occurrence 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

Pantozol, enteric-coated tablets, should be taken whole, 1 hour before a meal; the tablets must not be chewed or crushed, and should be swallowed with water.

Recommended Dosage

Adults and children aged 12 years and older

Treatment of reflux esophagitis

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

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

Adults

Eradication of H. pylori in combination with two antibiotics

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

a) 1 tablet of Pantozol 40 mg twice daily

1000 mg amoxicillin twice daily
500 mg clarithromycin twice daily

b) 1 tablet of Pantozol 40 mg twice daily

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

c) 1 tablet of Pantozol 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 Pantozol should be taken in the evening, 1 hour before a meal. The treatment duration is 7 days and may be extended up to 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), monotherapy with Pantozol should be administered at the dosage specified below.

Treatment of gastric ulcer
1 tablet of Pantozol per day. In individual cases, the dose may be doubled (2 tablets of Pantozol per day), especially if there is no response to other medications.

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

Treatment of duodenal ulcer
1 tablet of Pantozol per day. In individual cases, the dose may be doubled (2 tablets of Pantozol per day), especially if there is no response to other medications.

Treatment of duodenal ulcer usually requires 2 weeks. If this is insufficient, healing may be expected during the following 2 weeks.

Treatment of Zollinger-Ellison syndrome and other hypersecretory conditions
For long-term treatment of Zollinger-Ellison syndrome and other hypersecretory conditions, the initial daily dose is 80 mg (2 tablets of Pantozol 40 mg). If necessary, the dose may subsequently be titrated up or down based on gastric acid secretion parameters. Doses exceeding 80 mg per day should be divided into two administrations. Temporary dose increases above 160 mg of pantoprazole may be possible, 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.

Patients with hepatic impairment
In patients with severe hepatic impairment, the daily dose should not exceed 20 mg. Pantozol should not be used in patients with moderate to severe hepatic impairment for H. pylori eradication in combination therapy, as there are currently no data on the efficacy and safety of such use.

Patients with renal impairment
Dose adjustment is not required in patients with impaired renal function. However, Pantozol should not be used for H. pylori eradication in combination therapy in patients with renal impairment, as there are currently no data on the efficacy and safety of such use.

Elderly patients do not require dose adjustment.

Children

Pantozol is indicated in children aged 12 years and older for the treatment of reflux esophagitis. The use of Pantozol is not recommended in children under 12 years of age, as data on safety and efficacy in this age group are limited.

Overdose

Symptoms of overdose in humans are unknown.

Doses up to 240 mg administered intravenously over 2 minutes were well tolerated. Since pantoprazole is highly bound to plasma proteins, 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 were observed in approximately 5% of patients. Undesirable effects are classified by frequency of occurrence into the following categories: 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), and not known (frequency cannot be determined 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 "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; not known – hyponatremia, hypomagnesemia (see section "Special precautions"), hypocalcemia^1, hypokalemia^1.

Psychiatric disorders:
Uncommon – sleep disorders; rare – depression (including exacerbation); very rare – confusion (including exacerbation); not known – hallucination; confusion (particularly in patients predisposed to such disorders, and exacerbation of these symptoms if present).

Nervous system disorders:
Uncommon – headache, dizziness; rare – taste disturbances; 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; not known – microscopic colitis.

Hepatobiliary disorders:
Uncommon – increased liver enzymes (transaminases, gamma-glutamyl transferase); rare – increased bilirubin levels; not known – hepatocellular injury, jaundice, hepatocellular failure.

Skin and subcutaneous tissue disorders:
Uncommon – skin rashes, exanthema, pruritus; rare – urticaria, angioneurotic edema; not known – Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme, photosensitivity, 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; not known – muscle spasms^2.

Renal and urinary disorders:
Not known – tubulointerstitial 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 and/or hypokalemia may be associated with hypomagnesemia (see section "Special precautions").
^2 Muscle spasms as a consequence of electrolyte imbalance.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk profile of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging. Keep out of reach of children.

Packaging.

10 tablets per blister. 1, 2, or 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

"Unique Pharmaceutical Laboratories" (a division of "J. B. Chemicals & Pharmaceuticals Ltd.") / Unique Pharmaceutical Laboratories (a division of J. B. Chemicals & Pharmaceuticals Ltd.).

Manufacturer's address.

Plot No. 215-219, G.I.D.C., Industrial Area, Panoli - 394 116, Dist. Bharuch, India.