Pantor 40

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PANTOR 20, PANTOR 40 (PANTOR 20, PANTOR 40)

Composition:

Active substance: 1 tablet contains pantoprazole sodium sesquihydrate equivalent to pantoprazole 20 mg or 40 mg;

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

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties: oval, biconvex, enteric-coated tablets of yellow color, smooth on both sides.

Pharmacotherapeutic group. Drugs for treatment of peptic ulcer; proton pump inhibitor. 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. The inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. In most patients, symptoms resolve within 2 weeks. The use of pantoprazole, as with other proton pump inhibitors (PPIs) and H2-receptor antagonists, reduces gastric acidity and consequently increases gastrin secretion proportionally to the reduction in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds the enzyme distal to the cellular receptor, it can inhibit gastric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is equivalent following oral or intravenous administration.

Administration of pantoprazole increases fasting gastrin levels. With short-term use, gastrin levels in most cases do not exceed the upper limit of normal. With long-term treatment, gastrin levels typically increase twofold, with excessive elevation observed only in isolated cases. As a consequence, prolonged therapy may occasionally lead to mild or moderate increase in gastric enterochromaffin-like (ECL) cells (similar to adenomatoid hyperplasia). However, according to studies conducted to date, the development of precursor cells of neuroendocrine tumors (atypical hyperplasia) or gastric neuroendocrine tumors, observed in animal studies, has not been reported in humans.

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

Pharmacokinetics.

Absorption. Pantoprazole is rapidly absorbed, and its maximum plasma concentration (Cmax) is achieved after a single oral dose of 20 mg. On average, Cmax of approximately 1–1.5 µg/mL is reached within 2–2.5 hours after administration; plasma concentrations remain consistent with repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. Within the dose range of 10 to 80 mg, the pharmacokinetics of pantoprazole in plasma remain linear, both after oral administration and intravenous infusion. Absolute bioavailability of the tablets is approximately 77%. Concomitant food intake does not affect the area under the concentration-time curve (AUC) or Cmax, and thus does not alter bioavailability. However, food intake increases only the variability of the lag time.

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

Biological transformation. The substance is almost exclusively metabolized in the liver. The main metabolic pathway is demethylation via CYP2C19, followed by sulfation. Other metabolic pathways include 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 (approximately 80%), the remainder in feces. The main metabolite in both plasma and urine is desmethylpantoprazole sulfate conjugate. The elimination half-life of the main metabolite (approximately 1.5 hours) is slightly longer than that of pantoprazole.

Special patient groups.

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

Renal impairment. No dosage adjustment is recommended for patients with renal impairment (including patients on dialysis). As in healthy individuals, 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 no accumulation occurs.

Hepatic impairment. Although in patients with liver cirrhosis (Child-Pugh classes A and B) the elimination half-life increases to 3–6 hours and AUC increases 3–5 times, Cmax increases only slightly—by 1.5 times—compared to healthy volunteers.

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

Children. After a single oral dose of 20 or 40 mg of 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 in children aged 2 to 16 years, no significant relationship between pantoprazole clearance and patient age or body weight was observed. AUC and volume of distribution were consistent with data obtained in adult studies.

Clinical characteristics.

Indications.

Tablets 20 mg

Adults and children aged 12 years and older:

• symptomatic treatment of gastroesophageal reflux disease;
• long-term treatment and prevention of recurrence of reflux esophagitis.

Adults:

• prevention of gastric and duodenal ulcer induced by nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in patients at risk who require long-term NSAID therapy.

Tablets 40 mg

Adults and children aged 12 years and older:

• reflux esophagitis.

Adults:

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

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Medicinal products whose absorption depends on pH. Due to complete and prolonged inhibition of hydrochloric acid secretion, pantoprazole may affect the absorption of drugs for which gastric juice pH is an important factor in their bioavailability (e.g., certain antifungal agents such as ketoconazole, itraconazole, posaconazole, or other drugs such as erlotinib).

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

If concomitant use of HIV protease inhibitors with PPIs cannot be avoided, careful clinical monitoring (e.g., viral load) is recommended. The daily dose of pantoprazole should not exceed 20 mg. Dose adjustment of HIV protease inhibitors may be necessary.

Coumarin anticoagulants (phenprocoumon and warfarin). Concomitant use of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon, or the international normalized ratio (INR). However, there have been reports of increased INR and prolonged prothrombin time in patients receiving PPIs concomitantly with warfarin or phenprocoumon. Increased INR and prolonged prothrombin time may lead to severe bleeding and even fatal outcomes. Therefore, monitoring of INR and prothrombin time is necessary when these drugs are used concomitantly.

Methotrexate. It has been observed that concomitant administration of high-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 predominantly metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19, with additional metabolism via CYP3A4. Studies with drugs that are also metabolized via these pathways—such as carbamazepine, diazepam, glyburide, nifedipine, phenprocoumon, 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 several studies on potential interactions indicate that pantoprazole does not affect the metabolism of active substances metabolized by CYP1A2 (e.g., caffeine, theophylline), CYP2C9 (e.g., piroxicam, diclofenac, naproxen), CYP2D6 (e.g., metoprolol), or CYP2E1 (e.g., ethanol), and does not affect P-glycoprotein associated with digoxin absorption.

No interaction has been observed with concomitantly administered antacids.

Studies on pantoprazole interaction with concomitantly administered certain antibiotics (clarithromycin, metronidazole, amoxicillin) have been conducted. No clinically significant interactions were observed between these drugs.

Drugs 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 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 rise, 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), as well as in suspicion of or confirmed 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 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 secretion, may reduce absorption of vitamin B12 (cyanocobalamin) due to the development of hypo- or achlorhydria. This should be considered in patients with weight loss or risk factors for reduced vitamin B12 absorption during long-term treatment, or in the presence of corresponding clinical symptoms.

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

Gastrointestinal infections caused by bacteria. Treatment with the drug 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 mostly after one year of treatment. Serious clinical manifestations of hypomagnesemia, which may initially develop insidiously, include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia. Hypomagnesemia may lead to the development of hypocalcemia and/or hypokalemia (see section "Undesirable effects"). In cases of hypomagnesemia (and hypocalcemia and/or hypokalemia associated with hypomagnesemia), patients' condition improved in most cases after replacement therapy with magnesium supplements and discontinuation of PPI.

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 initiating PPI treatment and periodically during treatment.

Bone fractures. Long-term treatment (more than one year) with high doses of PPIs may slightly increase the risk of fractures of the hip, wrist, and spine, particularly in elderly patients or those with other risk factors. Observational studies suggest 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. Severe cutaneous adverse reactions associated with pantoprazole use have been reported with unknown frequency (see section "Undesirable effects"), 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 indicating these reactions occur, pantoprazole should be discontinued immediately and alternative treatment considered.

Subacute cutaneous lupus erythematosus. PPI use has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions develop, particularly in sun-exposed areas, and are accompanied by arthralgia, the patient should seek immediate medical advice, and discontinuation of the drug should be considered. Development of subacute cutaneous lupus erythematosus in patients during prior therapy with proton pump inhibitors may increase the risk of its recurrence when using 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 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. The 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 the drug in pregnant women (approximately 300–1000 reports on pregnancy outcomes) indicate no embryonal or fetoneonatal toxicity of the drug. Reproductive toxicity was observed in animal studies. As a precautionary measure, use of the drug in pregnant women should be avoided.

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

Method of Administration and Dosage.

Pantor 20 and Pantor 40, enteric-coated tablets, should be taken whole, 1 hour before a meal, without chewing or crushing, with a glass of water.

20 mg tablets

Recommended dosage.

Adults and children aged 12 years and older.

Symptomatic treatment of gastroesophageal reflux disease.

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

Long-term treatment and prevention of relapses of reflux esophagitis.

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

Adults.

Prevention of gastric and duodenal ulcers associated with long-term use of non-selective NSAIDs in patients at risk who require prolonged NSAID therapy.

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

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

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

Elderly patients do not require dose adjustment.

40 mg tablets

Recommended dosage.

Adults and children aged 12 years and older.

Treatment of reflux esophagitis.

The recommended dose for children aged 12 years and older and adults is 1 tablet (40 mg) once daily. In some cases, the dose may be doubled (2 tablets 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 within the next 4 weeks.

Adults.

Eradiation 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 appropriate antibiotic selection and use should be considered. Depending on susceptibility, the following therapeutic regimens may be prescribed for H. pylori eradication in adults:

a) 1 tablet of Pantor 40 mg twice daily

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

b) 1 tablet of Pantor 40 mg twice daily

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

c) 1 tablet of Pantor 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 Pantor 40 mg should be taken in the evening, 1 hour before a meal. The duration of treatment is 7 days and may be extended by another 7 days, with a total treatment duration not exceeding two weeks. If further treatment with pantoprazole is indicated to ensure ulcer healing, refer to the recommended dosage for gastric and duodenal ulcers. If combination therapy is not indicated, e.g., in patients with a negative H. pylori test, Pantor 40 may be used as monotherapy at the dosage specified below.

Treatment of gastric ulcer.

1 tablet of Pantor 40 mg once daily. In some cases, the dose may be doubled (2 tablets of Pantor 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 within the next 4 weeks.

Treatment of duodenal ulcer.

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

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 Pantor 40 mg). If necessary, the dose may subsequently be titrated up or down based 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 such treatment should be limited to the period required for adequate acid control.

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

Patients with hepatic impairment. Patients with severe hepatic impairment should not exceed a daily dose of 20 mg (1 tablet of Pantor 20 mg). Pantor 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 in this patient group.

Patients with renal impairment. Dose adjustment is not required in patients with renal impairment. Pantor 20 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 in this patient group.

Elderly patients do not require dose adjustment.

Children.

The drug 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 treatment should be administered. There are no specific antidotes or recommended specific therapies.

Adverse Reactions

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

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 (≥ 1/10000 and < 1/1000), very rare (< 1/10000), and not known (frequency cannot be estimated from available data). For all adverse reactions reported during the post-marketing period, the frequency cannot be determined; therefore, they are listed as "not known".

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 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, as well as 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, abdominal distension, 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 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 the development of hypomagnesemia (see section "Special precautions").

^2 Muscle spasms as a result of electrolyte imbalance.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets per blister, 1 or 3 blisters per cardboard pack.

Prescription category. Prescription only.

Manufacturer.

Torrent Pharmaceuticals Ltd.

Manufacturer's address and location of its business operations.

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