PANTOPRAZOLE

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

Composition:

Active substance: pantoprazole;

1 tablet contains sodium pantoprazole sesquihydrate equivalent to 40 mg of pantoprazole;

Excipients: anhydrous sodium carbonate, mannite (E 421), sucrose, talc, calcium stearate, silicon dioxide, hypromellose, macrogol, methacrylate copolymer (type A), triethyl citrate, titanium dioxide (E 171), red iron oxide (E 172), black iron oxide (E 172), Opacode black ink (shellac, isopropyl alcohol, iron oxide (E 172), butyl alcohol, propylene glycol, ammonium hydroxide).

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties: tablets are light pink to pinkish-brown in color, biconvex, oval-shaped, coated, with "P40" imprinted on one side and smooth on the other.

Pharmacotherapeutic group.

Drug for the treatment of acid-related disorders. 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, thus blocking the final step of gastric acid production. Inhibition is dose-dependent and affects both basal and stimulated acid secretion. Most patients are relieved of symptoms within 2 weeks. As with other PPIs and H2-receptor antagonists, pantoprazole reduces gastric acidity and thereby increases gastrin secretion proportionally to the reduction in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds 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 the same following oral or intravenous administration.

With pantoprazole use, fasting gastrin levels increase. With short-term use, gastrin levels generally remain within the upper normal range. With long-term treatment, gastrin levels typically double. Marked elevation occurs only in isolated cases. As a consequence, a small number of patients undergoing long-term treatment may develop mild or moderate increase in gastric enterochromaffin-like (ECL) cells (similar to adenomatoid hyperplasia). However, according to studies conducted to date, 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 studies, a potential effect of long-term (more than one year) pantoprazole treatment on thyroid gland endocrine parameters cannot be 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 increase. Elevated CgA levels may interfere with diagnostic testing for neuroendocrine tumors. Available published data indicate that PPI treatment should be discontinued for a period of 5 days to 2 weeks before measuring CgA levels. This allows CgA levels to return to the normal range, as they may be falsely elevated after PPI treatment.

Pharmacokinetics.

Absorption. Pantoprazole is rapidly absorbed, and maximum plasma concentration (Cmax) is achieved after a single oral dose of 40 mg. On average, Cmax of approximately 2–3 µg/mL is reached within 2.5 hours after administration; 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 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 the variability of the lag time.

Distribution. Plasma protein binding of pantoprazole is approximately 98%. The 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 sulfation; another metabolic pathway involves oxidation via CYP3A4.

Elimination. The terminal elimination half-life is approximately 1 hour, and clearance is about 0.1 L/h/kg. Several 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 pharmacological effect (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 elimination 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 have functional deficiency of CYP2C19 enzyme activity 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 Cmax increased by about 60%. These findings do not affect pantoprazole dosing recommendations.

Renal impairment.

No dose adjustment is recommended when prescribing pantoprazole to 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. Although the main metabolite has a moderately prolonged half-life (2–3 hours), elimination remains rapid, and no accumulation occurs.

Hepatic impairment.

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

Elderly patients.

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

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 0.8 or 1.6 mg/kg pantoprazole 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 were consistent with data obtained in adults.

Clinical characteristics.

Indications.

Adults and children aged 12 years and older.

• Gastroesophageal reflux disease (GERD).

Adults.

• Eradication of Helicobacter pylori (H. pylori) in patients with H. pylori-associated gastric and duodenal ulcers, in combination with appropriate antibiotics.
• Duodenal ulcer.
• Gastric ulcer.
• Zollinger-Ellison syndrome and other hypersecretory conditions.

Contraindications.

Hypersensitivity to the active substance, benzimidazole derivatives, or to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Medicinal products whose absorption is pH-dependent. Pantoprazole may reduce the absorption of drugs whose bioavailability depends on gastric pH (e.g., certain antifungal agents such as ketoconazole, itraconazole, posaconazole, or other drugs such as erlotinib).

HIV protease inhibitors (atazanavir). Concomitant use of PPIs with atazanavir and other antiretroviral drugs whose absorption is pH-dependent may lead to a significant reduction in their bioavailability and affect their efficacy. Therefore, concomitant use of PPIs with atazanavir is not recommended. In cases where 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). Although no interaction was observed during clinical studies when pantoprazole was co-administered with phenprocoumon or warfarin, isolated cases of changes in INR (International Normalized Ratio) and prolonged prothrombin time have been reported in the post-marketing period in patients receiving PPIs concomitantly with warfarin or phenprocoumon. Increased INR and prolonged prothrombin time may lead to pathological bleeding and even fatal outcomes. Therefore, patients receiving coumarin anticoagulants (e.g., phenprocoumon and warfarin) should be monitored for prothrombin time/INR upon initiation, discontinuation, or irregular use of pantoprazole.

Methotrexate. Concurrent use of high-dose methotrexate (e.g., 300 mg) and PPIs has been reported to increase 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 metabolism via other pathways, including oxidation by CYP3A4. Studies with drugs that are 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 excluded.

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

No interaction has been observed with concomitantly administered antacids.

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

Medicinal products that inhibit or induce CYP2C19.

CYP2C19 inhibitors, such as fluvoxamine, may increase the systemic exposure to pantoprazole. Consideration should be given to dose reduction 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 via these enzyme systems.

Special precautions for use.

Hepatic impairment. Patients with severe liver dysfunction should have regular monitoring of liver enzymes, especially during prolonged treatment. If liver enzyme levels increase, treatment with the drug should be discontinued.

Combination therapy. During combination therapy, 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), as well as in suspicion of or presence of gastric ulcer, malignancy must be ruled out, since treatment with pantoprazole may mask symptoms and delay diagnosis.

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 hydrochloric 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 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, especially longer than one year, should be under regular medical supervision.

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

Hypomagnesemia. Cases of severe hypomagnesemia have been observed in patients treated with 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 arrhythmias. In cases of hypomagnesemia, the condition improved in most patients after 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 hypomagnesemia (e.g., diuretics), should have serum magnesium levels measured before starting PPI treatment and periodically during treatment.

Bone fractures. Long-term (more than one year) high-dose PPI therapy may slightly increase the risk of fractures of the hip, wrist, and spine, particularly 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 osteoporosis should receive treatment according to current clinical guidelines and should consume adequate amounts 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, especially 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 SCLE in patients during prior PPI therapy may increase the risk of recurrence with other PPIs.

Effect on laboratory test results.

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

Excipients.

The tablets contain mannitol, which may have a mild laxative effect.

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 the drug. 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 are available on excretion of pantoprazole into human breast milk. The decision to discontinue breastfeeding or to discontinue/abstain from pantoprazole treatment should be made taking into account the benefit of breastfeeding for the child and the benefit of pantoprazole treatment for the woman.

Fertility.

Pantoprazole did not impair fertility in animal studies.

Ability to affect reaction speed when driving or operating machinery.

Pantoprazole does not affect 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. In such cases, driving or operating machinery should be avoided.

Method of Administration and Dosage

Pantoprazole enteric-coated tablets should be taken whole, one hour before a meal, without chewing or crushing, and with water.

Recommended Dosage

Adults and children aged 12 years and older

Treatment of reflux esophagitis.

The recommended dose is 1 tablet of Pantoprazole 40 mg once daily. In some cases, the dose may be doubled (2 tablets of Pantoprazole 40 mg daily), particularly if there is no response to other treatments for reflux esophagitis. Treatment of reflux esophagitis usually requires 4 weeks. If this is insufficient, healing may be expected 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 prescription and use of 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 Pantoprazole 40 mg twice daily

• 1000 mg amoxicillin twice daily
• 500 mg clarithromycin twice daily;

b) 1 tablet of Pantoprazole 40 mg twice daily

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

c) 1 tablet of Pantoprazole 40 mg twice daily

• 1000 mg amoxicillin twice daily
• 400–500 mg metronidazole (or 500 mg tinidazole) twice daily.

When using combination therapy for H. pylori eradication, the second tablet of Pantoprazole 40 mg should be taken in the evening, one hour before a meal. The treatment duration is 7 days and may be extended for another 7 days, with a total treatment duration not exceeding two weeks. If further treatment with pantoprazole is indicated to ensure ulcer healing, dosage recommendations for gastric and duodenal ulcers should be considered. If combination therapy is not indicated, for example in patients with a negative H. pylori test, monotherapy with Pantoprazole 40 mg should be used at the dosage specified below.

Treatment of gastric ulcer.

1 tablet of Pantoprazole 40 mg once daily. In some cases, the dose may be doubled (2 tablets of Pantoprazole 40 mg daily), particularly if there is no response to other treatments.

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

Treatment of duodenal ulcer.

1 tablet of Pantoprazole 40 mg once daily. In some cases, the dose may be doubled (2 tablets of Pantoprazole 40 mg daily), particularly if there is no response to other treatments.

Treatment of duodenal ulcer usually requires 2 weeks. If this is insufficient, ulcer 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 Pantoprazole 40 mg). If necessary, the dose may be subsequently titrated up or down depending on gastric acid secretion levels. Doses exceeding 80 mg daily should be divided into two doses. Temporary dose increases above 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 treatment duration 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 (1 tablet of Pantoprazole 20 mg). Pantoprazole should not be used for H. pylori eradication in combination therapy in patients with moderate to severe hepatic impairment, as there are currently no data on the efficacy and safety of such use in this patient group.

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

Elderly patients do not require dose adjustment.

Children.

Pantoprazole 40 mg is indicated for children aged 12 years and older for the treatment of reflux esophagitis. The use of the drug 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 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 can be easily removed by dialysis.

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

Side effects

Adverse reactions have been observed in approximately 5% of patients. The most common adverse reactions are diarrhea and headache (approximately 1%).

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

For all adverse reactions reported during the post-marketing period, 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), change 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: confusion (including exacerbation).

Frequency not known: hallucination, confusion (particularly in patients predisposed to such disorders, as well as exacerbation of these symptoms if pre-existing).

Nervous system disorders.

Uncommon: headache, dizziness.

Rare: taste disturbances.

Frequency not known: paraesthesia.

Eye disorders.

Rare: visual disturbances/blurry 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 rash, exanthema, pruritus.

Rare: urticaria, angioneurotic edema.

Frequency not known: Stevens-Johnson syndrome, Lyell's syndrome, 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.

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 occurring simultaneously with hypomagnesemia.
^2 Muscle spasms as a consequence of electrolyte imbalance.

Reporting of suspected adverse reactions.

It is important to report suspected adverse reactions after the medicinal product has been authorized. This allows continued monitoring of the benefit-risk balance. Healthcare professionals are encouraged to report suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in a place inaccessible to children at a temperature not exceeding 25 °C.

Packaging.

10 tablets in aluminum blisters. 1 or 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Jubilant Generics Limited.