INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PANTOPRAZOLE 40 (PANOCID 40)

Composition:

Active substance: One coated tablet contains sodium pantoprazole hemihydrate equivalent to 40 mg of pantoprazole;

Excipients: mannite (E 421), anhydrous sodium carbonate, crospovidone, hydroxypropylmethylcellulose, calcium stearate, colouring agent IC-S-329 (hydroxypropylmethylcellulose, polyethylene glycol), colouring agent ENS-II-041 (methacrylate copolymer (type C), polyethylene glycol, talc, titanium dioxide (E 171), yellow iron oxide (E 172)).

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties: yellow, round, biconvex enteric-coated tablets.

Pharmacotherapeutic group. Drugs for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. ATC code A02BC02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Pantoprazole is a substituted benzimidazole that inhibits gastric acid secretion by specifically blocking 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 hydrochloric 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 well as other proton pump inhibitors (PPIs) and H2-receptor antagonists, reduces gastric acidity and consequently increases gastrin secretion proportionally to the reduction in acidity. Increased 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 of oral and intravenous administration of the drug is equivalent.

Administration of pantoprazole increases fasting gastrin levels. With short-term use, 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, mild or moderate increase in specific enterochromaffin-like (ECL) cells in the stomach (similar to adenomatoid hyperplasia) may occasionally be observed during prolonged therapy. However, according to studies conducted to date, development of neuroendocrine tumor precursors (atypical hyperplasia) or gastric neuroendocrine tumors, observed in animal studies, has not been reported in humans.

Based on animal study results, a potential effect of long-term (more than one year) pantoprazole treatment on thyroid endocrine parameters cannot be completely ruled out.

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to 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 therapy should be discontinued for a period of 5 days to 2 weeks prior to CgA measurements. This allows CgA levels, which may be falsely elevated after PPI therapy, to return to normal ranges.

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 stable with repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. Within the dose range of 10 to 80 mg, pantoprazole pharmacokinetics in plasma remain linear, both after oral administration and intravenous infusion. Absolute bioavailability of pantoprazole in tablets is approximately 77%. Concomitant food intake does not affect AUC (area under the concentration-time curve) or Cmax, and thus does not affect bioavailability. Food intake only increases variability in the latency period.

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

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

Elimination. Terminal half-life is approximately 1 hour, and clearance is 0.1 L/h/kg. A few cases of delayed elimination have been observed. Due to the specific binding of pantoprazole to proton pumps in parietal cells, the elimination half-life does not correlate with the much longer duration of 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 serum and urine is desmethylpantoprazole sulfate conjugate. The half-life of the main metabolite (approximately 1.5 hours) is only slightly longer than that of pantoprazole.

Special patient groups.

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

Renal impairment. No dosage adjustment recommendations are required for pantoprazole administration in 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 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, 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 is also not clinically significant.

Children. After a single oral dose of 20 or 40 mg pantoprazole, AUC and Cmax in children aged 5 to 16 years were within the range observed in adults. After a single intravenous dose of 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 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) with 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 the active substance, benzimidazole derivatives, or to any component of the medicinal product.

Interaction with other medicinal products and other forms of interactions.

Medicinal products whose absorption is pH-dependent. Due to complete and prolonged inhibition of gastric acid secretion, pantoprazole may affect the absorption of medicinal products 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 dependent on intragastric pH, is not recommended due to a significant reduction in their bioavailability.

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 use 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 reported that concomitant administration 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 and other pathways. Studies with drugs metabolized by these same 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 ruled out.

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

No interaction has been observed with concurrently administered antacids.

Studies investigating potential interactions between pantoprazole and certain concurrently administered antibiotics (clarithromycin, metronidazole, amoxicillin) have not revealed 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 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.

Interaction between medicinal products and laboratory tests. False-positive urine screening tests for tetrahydrocannabinol have been reported in patients taking pantoprazole. Alternative testing methods should be considered to confirm 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 method of administration").

Combination therapy. When using combination therapy, the instructions for medical use of the respective 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, haematemesis, 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 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 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 weight or risk factors for reduced vitamin B12 absorption during long-term treatment, or in the presence of corresponding clinical symptoms.

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

Gastrointestinal infections caused by bacteria. Treatment with Panozid 40 may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile.

Hypomagnesaemia. Rare 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, which may develop initially unnoticed, include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. Hypomagnesaemia may lead to the development of hypocalcaemia and/or hypokalaemia (see section "Undesirable effects"). In cases of hypomagnesaemia (and hypocalcaemia and/or hypokalaemia associated with hypomagnesaemia), the condition of patients improved in most cases after corrective magnesium replacement therapy 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 starting PPI treatment and periodically during therapy.

Bone fractures. Long-term (more than one year) high-dose PPI treatment may moderately increase the risk of fractures of the hip, wrist, and spine, particularly in elderly patients or those with other risk factors. Observational studies indicate that PPI use may increase the overall risk of fractures by 10–40%. Some of these 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.

Severe cutaneous adverse reactions (SCAR). Severe cutaneous adverse reactions associated with pantoprazole use, with unknown frequency (see section "Undesirable effects"), potentially life-threatening or fatal, such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported. 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 treatment considered.

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 the drug should be considered. Development of subacute cutaneous lupus erythematosus 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 this interference, treatment with the medicinal product should be temporarily discontinued at least 5 days before assessment of CgA levels (see section "Pharmacodynamics"). If CgA and gastrin levels have not returned to normal range after initial measurement, repeat measurements should be performed 14 days after discontinuation of PPI treatment.

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

Use during pregnancy or breastfeeding.

Pregnancy. Available data on the use of pantoprazole in pregnant women (approximately 300–1000 pregnancy outcomes reported) indicate no embryonal or fetotoxic/neonatal toxicity of the drug. 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 to the child and the benefit of therapy to the woman.

Fertility. Pantoprazole did not impair fertility in animal studies.

Ability to influence the speed of reaction when driving or operating machinery.

Pantoprazole has no effect or a negligible effect on the ability to drive or operate machinery. However, the possible occurrence of adverse reactions such as dizziness and visual disturbances should be taken into account. In such cases, driving or operating machinery should be avoided.

Method of administration and dosage.

Tablets should be taken whole, 1 hour before a meal, without chewing or crushing, with water.

Recommended dosage.

Adults and children aged 12 years and older.

Treatment of reflux esophagitis.

The recommended dose is 1 tablet daily. In individual cases, the dose may be doubled (2 tablets daily), 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 within the next 4 weeks.

Adults.

Eradication of H. pylori in combination with two antibiotics.

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

a) 1 tablet of Panocid 40 (40 mg) twice daily

1000 mg amoxicillin twice daily
500 mg clarithromycin twice daily;

b) 1 tablet of Panocid 40 (40 mg) twice daily

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

c) 1 tablet of Panocid 40 (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 should be taken in the evening, 1 hour before a meal. The duration of treatment is 7 days and may be extended for another 7 days. The total treatment duration should not exceed two 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 Panocid 40 (40 mg) should be administered at the dosage specified below.

Treatment of gastric ulcer.

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

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

Treatment of duodenal ulcer.

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

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

Treatment of Zollinger–Ellison syndrome and other hypersecretory conditions.

For long-term treatment of Zollinger–Ellison syndrome and other hypersecretory conditions, the initial daily dose is 80 mg (2 tablets of Panocid 40 (40 mg)). If necessary, the dose may subsequently be titrated up or down depending on gastric acid secretion parameters. Doses exceeding 80 mg daily should be divided into two doses. A temporary increase in dose to more than 160 mg of pantoprazole may be possible, but the duration of use should be limited only 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 liver dysfunction, the daily dose should not exceed 20 mg. The drug 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 group.

Patients with renal impairment. Dose adjustment is not required in patients with renal impairment. The drug 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 group.

Elderly patients do not require dose adjustment.

Children.

Panocid 40 is indicated for children aged 12 years and older for the treatment of reflux esophagitis. 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 therapy should be administered. There are no recommendations for specific antidotal treatment.

Adverse reactions.

Adverse reactions have been observed in approximately 5% of patients.

Undesirable effects are classified by frequency of occurrence as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), 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 "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 for use"), hypocalcemia¹, hypokalemia¹.

Psychiatric disorders.

Uncommon: sleep disorders.

Rare: depression (including exacerbation).

Very rare: disorientation (including exacerbation).

Not known: hallucination, 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.

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.

Not known: microscopic colitis.

Hepatobiliary disorders.

Uncommon: increased liver enzymes (transaminases, γ-GT).

Rare: increased bilirubin levels.

Not known: hepatocellular injury, jaundice, hepatocellular insufficiency.

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 for use").

Musculoskeletal and connective tissue disorders.

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

Rare: arthralgia, myalgia.

Not known: muscle spasms².

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 the development of hypomagnesemia (see section "Special precautions for use").

² Muscle spasms as a consequence of electrolyte imbalance.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug registration 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.

Keep out of reach of children.

Store at temperatures not exceeding 30 °C in the original packaging.

Packaging. 10 tablets per blister. 1 or 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

Ananta Medicare Limited.

Manufacturer's address and place of business.

Chak 17 ML, Agro Food Park Road, RIICO Industrial Area, Udaipurwati, Sri Ganganagar-335002 (Rajasthan), India.

Marketing Authorisation Holder.

Ananta Medicare Ltd.

Address of Marketing Authorisation Holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.

INSTRUCTIONS

for medical use of the medicinal product

PANOZID 40

(PANOCID 40)

Composition:

Active substance: 1 coated tablet contains sodium pantoprazole hemihydrate equivalent to pantoprazole 40 mg;

Excipients: mannite (E 421), anhydrous sodium carbonate, crospovidone, hydroxypropylmethylcellulose, calcium stearate, colorant IC-S-329 (hydroxypropylmethylcellulose, polyethylene glycol), colorant ENS-II-041 (methacrylate copolymer (type C), polyethylene glycol, talc, titanium dioxide (E 171), yellow iron oxide (E 172)).

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties: yellow, round, biconvex tablets with an enteric coating.

Pharmacotherapeutic group. Drugs for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. ATC code A02BC02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Pantoprazole is a substituted benzimidazole that inhibits gastric acid secretion by specifically blocking 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 acid production. The 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 (PPIs) and H₂-receptor antagonists, pantoprazole reduces gastric acidity and consequently increases gastrin secretion proportionally to the reduction in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds to the enzyme distal to the cellular receptor, it can inhibit gastric 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, levels usually remain within the upper normal range. With long-term treatment, gastrin levels typically double. Marked elevation occurs only in isolated cases. As a result, prolonged therapy may occasionally lead to mild or moderate increase in gastric enterochromaffin-like (ECL) cells (similar to adenomatoid hyperplasia). However, according to available studies to date, development of neuroendocrine tumor precursors (atypical hyperplasia) or gastric neuroendocrine tumors, observed in animal studies, has not been reported in humans.

Based on animal study results, a potential effect of long-term (more than one year) pantoprazole treatment on thyroid endocrine parameters cannot be completely ruled out.

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels rise. Elevated CgA levels may interfere with diagnostic testing for neuroendocrine tumors. Published data indicate that PPI therapy 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 (C_max) is achieved after a single 40 mg oral dose. On average, peak serum concentration of approximately 2–3 µg/mL is reached within 2.5 hours after administration; plasma concentrations remain stable with repeated dosing. Pharmacokinetic properties are unchanged after single or repeated doses. Within the dose range of 10 to 80 mg, pantoprazole pharmacokinetics in plasma remain linear, both after oral administration and intravenous infusion. Absolute bioavailability of pantoprazole in tablet form is approximately 77%. Concomitant food intake does not affect AUC (area under the concentration-time curve) or C_max, and thus does not affect bioavailability. Food intake only increases variability in the latency period.

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

Elimination. Terminal half-life is approximately 1 hour, and clearance is 0.1 L/h/kg. A few 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 serum and urine is desmethylpantoprazole sulfate conjugate. The half-life of the main metabolite (approximately 1.5 hours) is only slightly longer than that of pantoprazole.

Special patient groups.

Slow 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 catalyzed primarily 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 C_max 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 patients on dialysis). 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 accumulation does not occur.

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

Elderly patients. The slight increase in AUC and C_max observed in elderly volunteers compared to younger volunteers is 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 0.8 or 1.6 mg/kg pantoprazole in children aged 2 to 16 years, no significant relationship was observed between pantoprazole clearance and patient age or body weight. AUC and volume of distribution were comparable to those in adults.

Clinical characteristics.

Indications.

Adults and children aged 12 years and older.

Gastroesophageal reflux disease (GERD) with 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 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 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).

Coumarin anticoagulants (phenprocoumon and warfarin).
Concomitant use of pantoprazole with warfarin or phenprocoumon has not been shown to 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. Elevated INR and prolonged prothrombin time may lead to severe bleeding and even fatal outcomes. Therefore, INR and prothrombin time should be monitored closely when these agents are used together.

Methotrexate. There have been reports of increased methotrexate blood levels in some patients when high-dose methotrexate (e.g., 300 mg) is administered concomitantly with PPIs. 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 and other pathways. Studies with drugs also metabolized by these pathways—such as carbamazepine, diazepam, glibenclamide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—have not revealed clinically significant interactions.

Interactions between pantoprazole and other drugs metabolized by the same enzyme systems cannot be ruled out.

Results from multiple studies on potential interactions indicate that pantoprazole does not affect the metabolism of substances metabolized by CYP1A2 (e.g., caffeine, theophylline), CYP2C9 (e.g., piroxicam, diclofenac, naproxen), CYP2D6 (e.g., metoprolol), CYP2E1 (e.g., ethanol), nor does it affect P-glycoprotein associated with digoxin absorption.

No interaction has been observed with concomitantly administered antacids.

Studies investigating the interaction of pantoprazole with certain concomitantly administered antibiotics (clarithromycin, metronidazole, amoxicillin) have not revealed 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.

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 testing methods should be considered to confirm 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 drug must be discontinued (see section "Dosage and administration").

Combination therapy. During 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 (e.g. significant weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena), or suspicion or presence of 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 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 interaction").

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 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 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 one year, should be under regular medical supervision.

Gastrointestinal infections caused by bacteria. Treatment with Panocid 40 may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile.

Hypomagnesemia. Rare cases of severe hypomagnesemia 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 hypomagnesemia, which may develop insidiously, include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia. Hypomagnesemia may lead to the development of hypocalcemia and/or hypokalemia (see section "Adverse reactions"). In cases of hypomagnesemia (and hypocalcemia and/or hypokalemia associated with hypomagnesemia), 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 hypomagnesemia (e.g. diuretics), should have serum magnesium levels measured before starting PPI treatment and periodically during treatment.

Severe cutaneous adverse reactions (SCAR). Severe cutaneous adverse reactions associated with pantoprazole use, with unknown frequency, have been reported (see section "Adverse reactions"), which may be life-threatening or lead to fatal outcomes, 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 treatment considered.

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, accompanied by arthralgia, the patient should seek immediate medical advice, and discontinuation of the drug should be considered. Development of subacute cutaneous lupus erythematosus 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 testing for neuroendocrine tumors. To avoid such interference, treatment with the drug should be temporarily discontinued at least 5 days before CgA assessment (see section "Pharmacodynamics"). If CgA and gastrin levels have not returned to normal range after initial measurement, repeat measurements should be performed 14 days after discontinuation of PPI treatment.

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

Use during pregnancy or breastfeeding.

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

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. A decision on whether to discontinue breastfeeding or discontinue/abstain from pantoprazole treatment should be made taking into account the benefit of breastfeeding for the child and the benefit of treatment 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 the ability to drive or operate machinery. However, the possible development of adverse reactions such as dizziness and visual disturbances should be taken into account. In such cases, driving or operating machinery should be avoided.

Method of administration and dosage.

Tablets should be taken whole, 1 hour before meals, without chewing or crushing, with water.

Recommended dosage.

Adults and children aged 12 years and older.

Treatment of reflux esophagitis.

The recommended dose is 1 tablet per day. In individual cases, the dose may be doubled (2 tablets 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 within the next 4 weeks.

Adults.

Eradication of H. pylori in combination with two antibiotics.

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

a) 1 tablet of Panozyd 40 (40 mg) twice daily

1000 mg amoxicillin twice daily
500 mg clarithromycin twice daily;

b) 1 tablet of Panozyd 40 (40 mg) twice daily

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

c) 1 tablet of Panozyd 40 (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 should be taken in the evening, 1 hour before meals. The duration of treatment is 7 days and may be extended for another 7 days. The total treatment duration should not exceed two 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 Panozyd 40 (40 mg) should be administered at the dosage specified below.

Treatment of gastric ulcer.

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

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

Treatment of duodenal ulcer.

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

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

Treatment of Zollinger‒Ellison syndrome and other hypersecretory conditions.

For long-term treatment of Zollinger‒Ellison syndrome and other pathological hypersecretory states, the initial daily dose is 80 mg (2 tablets of Panozyd 40 (40 mg)). If necessary, the dose may subsequently be titrated up or down depending on gastric acid secretion levels. Doses exceeding 80 mg per day should be divided into two administrations. A temporary increase in dose to over 160 mg of pantoprazole may be possible, but the duration of use should be limited only 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.

Elderly patients do not require dose adjustment.

Children.

Panozyd 40 is indicated in children aged 12 years and older for the treatment of reflux esophagitis. The drug 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 a drug that is readily dialyzable.

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

Adverse Reactions

Adverse reactions were observed in approximately 5% of patients.

Undesirable effects are classified by frequency of occurrence as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), unknown (frequency cannot be estimated from available data).

For all adverse reactions reported during the post-marketing period, frequency cannot be determined; therefore, they are listed as "unknown".

Within each frequency category, adverse reactions are listed in decreasing order of 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 nutritional disorders.

Rare: hyperlipidemia and increased lipid levels (triglycerides, cholesterol), changes in body weight.

Unknown: hyponatremia, hypomagnesemia (see section "Special precautions for use"), hypocalcemia^1, hypokalemia^1.

Psychiatric disorders.

Uncommon: sleep disorders.

Rare: depression (including exacerbation).

Very rare: disorientation (including exacerbation).

Unknown: hallucination, confusion (particularly in patients predisposed to such disorders, and including exacerbation of pre-existing symptoms).

Nervous system disorders.

Uncommon: headache, dizziness.

Rare: taste disturbances.

Unknown: paresthesia.

Eye disorders.

Rare: visual disturbances/blurred vision.

Gastrointestinal disorders.

Common: fundic gland polyps (benign).

Uncommon: diarrhea, nausea, vomiting, abdominal distension, constipation, dry mouth, abdominal pain and discomfort.

Unknown: microscopic colitis.

Hepatobiliary disorders.

Uncommon: increased liver enzymes (transaminases, γ-GT).

Rare: increased bilirubin levels.

Unknown: hepatocellular injury, jaundice, hepatocellular failure.

Skin and subcutaneous tissue disorders.

Uncommon: skin rashes, exanthema, pruritus.

Rare: urticaria, angioneurotic edema.

Unknown: 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 for use").

Musculoskeletal and connective tissue disorders.

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

Rare: arthralgia, myalgia.

Unknown: muscle spasms^2.

Renal and urinary disorders.

Unknown: 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 for use").

^2 Muscle spasms as a consequence of electrolyte imbalance.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.

Keep out of reach of children.

Store at a temperature not exceeding 30 °C in the original packaging.

Packaging. 10 tablets per blister. 1 or 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

Flamingo Pharmaceuticals Ltd.

Manufacturer's address and place of business.

E-28, Opp. Fire Brigade, M.I.D.C., Talodha, Raigad District, Maharashtra, IN-410 208, India.

Marketing authorization holder.

Ananta Medicare Ltd.

Address of the marketing authorization holder and/or its representative.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.