Topraz

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TOBRAZ (TOPRAZ)

Composition:

Active substance: pantoprazole;

One gastro-resistant tablet contains pantoprazole sodium sesquihydrate equivalent to pantoprazole 40 mg;

Excipients: mannitol (E 421), crospovidone, anhydrous sodium carbonate, hypromellose, calcium stearate, hydroxypropylcellulose, yellow iron oxide (E 172), methacrylate copolymer dispersion, triethyl citrate.

Pharmaceutical form. Gastro-resistant tablets.

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

Pharmacotherapeutic group. Drugs for treatment of acid-related diseases. Proton pump inhibitors. ATC code A02BC02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Pantoprazole is a substituted benzimidazole that inhibits gastric hydrochloric acid secretion by specifically blocking the proton pumps of parietal cells. Pantoprazole is transformed into its active form in the acidic environment of parietal cells, where it inhibits the enzyme H⁺-K⁺-ATPase, thereby blocking the final step of gastric hydrochloric acid production. Inhibition is dose-dependent and affects both basal and stimulated acid secretion. Most patients are relieved of symptoms 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. This increase in gastrin secretion is reversible. Since pantoprazole binds to the enzyme distal to the cellular receptor, it can inhibit hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same following both oral and intravenous administration.

With pantoprazole use, fasting gastrin levels increase. With short-term use, levels in most cases 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, a small number of patients undergoing prolonged treatment may experience mild or moderate increase in gastric enterochromaffin-like (ECL) cells (similar to adenomatoid hyperplasia). However, according to available studies, the development of neuroendocrine tumor precursors (atypical hyperplasia) or gastric neuroendocrine tumors, as observed in animal studies, has not been reported in humans.

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

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels rise. Elevated CgA levels may interfere with diagnostic tests for neuroendocrine tumors. Published data indicate that PPI treatment should be discontinued for a period of 5 days to 2 weeks prior to CgA measurement. This allows CgA levels to return to the normal range, as they may be elevated following PPI therapy.

Pharmacokinetics.

Absorption. Pantoprazole is rapidly absorbed, and maximum plasma concentration (C_max) is achieved after a single 40 mg oral dose. On average, C_max of approximately 2–3 µg/mL is reached within 2.5 hours after administration; concentrations do not change with repeated dosing. Pharmacokinetic properties remain unchanged 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 the tablets 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 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.

Biological transformation. 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 half-life (T_1/2) is approximately 1 hour, and clearance is 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, T_1/2 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 half-life of the main metabolite (approximately 1.5 hours) is slightly longer than that of pantoprazole.

Special patient groups.

Slow metabolizers.

Approximately 3% of Europeans have low functional activity of the enzyme CYP2C19; these individuals are referred to as poor metabolizers. In such individuals, pantoprazole metabolism is likely primarily catalyzed 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 about 60%. These findings do not affect pantoprazole dosing.

Patients with renal impairment.

No dosage adjustment is recommended for pantoprazole in patients with impaired renal function, including those on dialysis. As in healthy individuals, the T_1/2 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 is rapid, so accumulation does not occur.

Patients with hepatic impairment.

Although in patients with liver cirrhosis (Child-Pugh classes A and B), T_1/2 increases to 7–9 hours and AUC increases 5–7 times, C_max increases only slightly—by 1.5 times—compared to healthy volunteers.

Elderly patients.

A slight increase in AUC and C_max 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 between pantoprazole clearance and age or body weight was observed. AUC and volume of distribution corresponded to data obtained in adult studies.

Clinical characteristics.

Indications.

Adults and children aged 12 years and older.

• Gastroesophageal reflux disease (GERD).

Adults.

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

Contraindications.

Hypersensitivity to the active substance, benzimidazole derivatives, or to any other 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 reduce the absorption of drugs whose bioavailability depends on gastric pH (e.g., certain azole 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 a significant reduction in their bioavailability (see section "Special warnings and precautions for use").

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

Coumarin anticoagulants (phenprocoumon and warfarin).

Concomitant use of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon, or INR (international normalized ratio). 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. Monitoring of INR and prothrombin time is required 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 predominantly 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 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. Interactions 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 active substances metabolized by CYP1A2 (e.g., caffeine, theophylline), CYP2C9 (e.g., piroxicam, diclofenac, naproxen), CYP2D6 (e.g., metoprolol), or CYP2E1 (e.g., ethanol). Pantoprazole does not interfere with P-glycoprotein-dependent digoxin absorption.

No interactions were observed with concomitantly administered antacids.

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

Medicinal products that inhibit or induce CYP2C19.

Inhibitors of CYP2C19, such as fluvoxamine, may increase the systemic exposure to pantoprazole. Dose reduction should be considered in patients receiving long-term, high-dose pantoprazole therapy and in patients with impaired liver function. Enzyme inducers affecting CYP2C19 and CYP3A4, such as rifampicin and St. John’s wort (Hypericum perforatum), may reduce plasma concentrations of PPIs metabolized via these enzyme systems.

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

Special precautions for use.

Hepatic impairment. In patients with severe hepatic impairment, liver enzymes should be monitored regularly, especially during long-term treatment. If liver enzyme levels increase, treatment with the medicinal product should be discontinued (see section "Dosage and administration").

Combination therapy. When combination therapy is used, the instructions for medical use of the respective medicinal products should be followed.

Concomitant use with NSAIDs.

The use of the medicinal product Topraz, gastro-resistant tablets 40 mg, for the prevention of gastric and duodenal ulcers associated with NSAID use should be limited to patients requiring continuous NSAID therapy and who are at increased risk of gastrointestinal complications.

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

Malignant gastric tumours. 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), as well as in suspected 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 other drugs that inhibit hydrochloric acid production, may reduce the 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 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 the medicinal product may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or Clostridium difficile.

Hypomagnesaemia. Rare cases of severe hypomagnesaemia have been reported in patients treated with proton pump inhibitors (PPIs), such as pantoprazole, for at least 3 months, and in most cases, for one year or longer. Serious clinical manifestations of hypomagnesaemia, which may initially be subtle and progress insidiously, include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia. Hypomagnesaemia may lead to the development of hypocalcaemia and/or hypokalaemia (see section "Adverse reactions"). In cases of hypomagnesaemia (and hypocalcaemia and/or hypokalaemia associated with hypomagnesaemia), the condition of patients usually improved after magnesium replacement therapy and discontinuation of PPI treatment.

In patients requiring long-term therapy and in those receiving PPIs concomitantly with digoxin or medications that may cause hypomagnesaemia (e.g., diuretics), serum magnesium levels should be measured before initiating PPI treatment and periodically during treatment.

Bone fractures. Long-term treatment (more than one year) with high doses of PPIs may moderately increase the risk of fractures of the hip, wrist, and spine, particularly in elderly patients or those with other risk factors. Observational studies indicate that PPI use increases the overall fracture risk by 10–40%. Some of these fractures may be attributable to other factors. Patients at risk of osteoporosis should receive treatment according to current clinical guidelines and consume adequate amounts of vitamin D and calcium.

Severe cutaneous adverse reactions. Severe cutaneous adverse reactions associated with pantoprazole use, with unknown frequency (see section "Adverse reactions"), 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 Topraz should be considered. Development of subacute cutaneous lupus erythematosus in patients during previous PPI therapy increases the risk of recurrence with other PPIs.

Effect on laboratory test results. Elevated chromogranin A (CgA) levels may interfere with diagnostic tests for neuroendocrine tumours. To avoid such interference, treatment with the medicinal product should be temporarily discontinued at least 5 days before CgA level 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.

Important information on excipients.

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

The medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. Available data on the use of pantoprazole 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, the use of Topraz in pregnant women should be avoided.

Breastfeeding. Animal studies have shown excretion of pantoprazole into breast milk. There is insufficient data on the excretion of pantoprazole into human breast milk, although such excretion has been reported. A risk to newborns/infants cannot be excluded. The decision to discontinue breastfeeding or to discontinue/abstain from treatment with Topraz should be made taking into account the benefit of breastfeeding for the child and the benefit of treatment with Topraz for the woman.

Fertility. Pantoprazole did not impair fertility in animal studies.

Ability to affect reaction speed when driving or operating machinery.

Pantoprazole has no effect or a negligible effect on the ability to drive or operate machinery. The possible development of adverse reactions such as dizziness and visual disturbances should be taken into account (see section "Adverse reactions"). In such cases, driving or operating machinery should be avoided.

Method of administration and dosage.

Topraz, gastro-resistant tablets, should be taken whole, one hour before a meal. Do not chew or crush the tablets. Swallow with water.

Recommended dosage.

Adults and children aged 12 years and older.

Treatment of reflux esophagitis.

The recommended dose is 1 tablet of Topraz 40 mg once daily. In individual cases, the dose may be doubled (2 tablets of Topraz 40 mg daily), especially if no response is observed with other treatments for reflux esophagitis. Treatment usually requires 4 weeks. If healing is not achieved within this period, it may be expected during the following 4 weeks.

Adults.

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

a) 1 tablet of Topraz 40 mg twice daily

• 1000 mg amoxicillin twice daily

• 500 mg clarithromycin twice daily;

b) 1 tablet of Topraz 40 mg twice daily

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

• 250–500 mg clarithromycin twice daily;

c) 1 tablet of Topraz 40 mg twice daily

• 1000 mg amoxicillin twice daily

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

When using combination therapy for H. pylori eradication, the second dose of Topraz 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, e.g., in patients with a negative H. pylori test, Topraz 40 mg may be used as monotherapy at the dosage specified below.

Treatment of gastric ulcer.

1 tablet of Topraz 40 mg once daily. In individual cases, the dose may be doubled (2 tablets of Topraz 40 mg daily), especially if no response is observed with other treatments.

Treatment of gastric ulcer usually requires 4 weeks. If healing is not achieved within this period, it may be expected during the following 4 weeks.

Treatment of duodenal ulcer.

1 tablet of Topraz 40 mg once daily. In individual cases, the dose may be doubled (2 tablets of Topraz 40 mg daily), especially if no response is observed with other treatments.

Treatment of duodenal ulcer usually requires 2 weeks. If healing is not achieved within this period, it 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 Topraz 40 mg). If necessary, the dose may be titrated up or down based on gastric acid secretion parameters. Doses exceeding 80 mg daily should be divided into two doses. A temporary dose increase beyond 160 mg of pantoprazole may be considered, but the duration of such treatment should be limited to the period required for adequate acid control.

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

Patients with hepatic impairment. In patients with severe hepatic impairment, the daily dose should not exceed 20 mg (1 tablet of Topraz 20 mg). Topraz 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. Topraz 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. No dose adjustment is required.

Children.

Topraz 40 mg 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 readily removable by dialysis.

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

Adverse Reactions

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

Undesirable 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), not known (frequency cannot be estimated from the available data).

The frequency of adverse reactions reported during the post-marketing period cannot be determined and therefore is 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: thrombocytopenia, leukopenia, 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.

Not known: 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).

Not known: hallucination, confusion (particularly in patients predisposed to such disorders, as well as exacerbation of these symptoms if present).

Nervous system disorders.

Uncommon: headache, dizziness.

Rare: taste disturbances.

Not known: paraesthesia.

Eye disorders.

Rare: visual disturbances / blurred vision.

Gastrointestinal disorders.

Common: fundic gland polyps (benign).

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

Not known: microscopic colitis.

Hepatobiliary disorders.

Uncommon: increased levels of liver enzymes (transaminases, γ-glutamyl transferase).

Rare: increased bilirubin levels.

Not known: hepatocellular injury, jaundice, hepatocellular failure.

Skin and subcutaneous tissue disorders.

Uncommon: skin rashes, exanthema, pruritus.

Rare: urticaria, angioneurotic edema.

Not known: Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special precautions 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 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 for use").

^2 Muscle spasms as a consequence of electrolyte imbalance.

Reporting of suspected adverse reactions.

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

Shelf life. 3 years.

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

Packaging. 10 tablets in a blister; 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

1. Aurobindo Pharma Limited - Unit VII.
2. Aurobindo Pharma Ltd, Formulation Unit XV.

Manufacturer's address and location of operations.

1. Special Economic Zone, TSIIC, Plot No. S1, Sy. No. 411/P, 425/P, 434/P, 435/P and 458/P, Green Industrial Park, Polepally Village, Jedcherla Mandal, Mahabubnagar District, Telangana State, 509302, India
2. Plot No. 17A, E. Bonganish (Village), Paravada (Mandal), Visakhapatnam, Andhra Pradesh, 531021, India