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

Composition:

Active substance: pantoprazole;

One gastro-resistant tablet contains pantoprazole sodium sesquihydrate equivalent to 20 mg of pantoprazole;

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

Pharmaceutical form. Gastro-resistant tablets.

Main physico-chemical characteristics: 20 mg tablets: light yellow, enteric-coated, oval biconvex tablets, smooth on both sides.

Pharmacotherapeutic group. Drugs 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, thereby blocking the final step of gastric hydrochloric acid production. Inhibition is dose-dependent and affects both basal and stimulated acid secretion. Most patients become symptom-free within 2 weeks. The use of pantoprazole, as well as other proton pump inhibitors (PPIs) and H2-receptor antagonists, reduces gastric acidity and thus 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 hydrochloric 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 treatment, 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, a small number of patients undergoing long-term treatment may experience mild or moderate increase in gastric enterochromaffin-like (ECL) cells (similar to adenomatoid hyperplasia). However, according to available studies, the formation of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors, observed in animal studies, has not been observed in humans.

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

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. In addition, 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 treatment should be discontinued for a period of 5 days to 2 weeks before measuring CgA levels. This allows CgA levels to return to normal, 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 20 mg. On average, Cmax of about 1–1.5 µg/mL is reached approximately 2–2.5 hours after administration; the concentration does not change after repeated dosing. Pharmacokinetic properties are unchanged 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 AUC (area under the concentration-time curve) or Cmax, and therefore does not affect bioavailability. Food intake only increases the variability of the lag time.

Distribution. Protein binding of pantoprazole to plasma proteins is about 98%. The volume of distribution is approximately 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 half-life (T1/2) 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 T1/2 does not reflect the much longer duration of action (acid secretion inhibition).

The majority of pantoprazole metabolites are excreted in urine (about 80%), the remainder in feces. The main metabolite in both plasma and urine is desmethylpantoprazole sulfate conjugate. The T1/2 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; these individuals are referred to as poor metabolizers. In these individuals, pantoprazole metabolism is likely primarily catalyzed by the CYP3A4 enzyme. After a single 40 mg dose, mean AUC was approximately 6 times higher in poor metabolizers than in individuals with functionally active CYP2C19 (extensive metabolizers). Mean Cmax increased by about 60%. These findings do not affect pantoprazole dosing.

Patients with renal impairment.

No dosage adjustment recommendations are necessary for pantoprazole in patients with impaired renal function, including those on dialysis. As in healthy individuals, the T1/2 of pantoprazole is short. Only very small amounts of pantoprazole are dialyzed. Although the main metabolite has a moderately prolonged T1/2 (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), the T1/2 increases to 3–6 hours and AUC increases 3–5 times, Cmax increases only slightly (by a factor of 1.3) 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 of values 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 corresponded to data obtained in adult studies.

Clinical characteristics.

Indications.

Adults and children aged 12 years and older.

Symptomatic treatment of gastroesophageal reflux disease.
Long-term treatment and prevention of relapses of reflux esophagitis.

Adults.

Prevention of gastric and duodenal ulcer associated with the use of non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) in patients at risk who require long-term NSAID therapy.

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 medicinal products 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 dependent on intragastric pH, 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. In such cases of concomitant use, monitoring of INR and prothrombin time is required.

Methotrexate.

There have been reports of increased blood levels of methotrexate 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; other metabolic pathways include oxidation by CYP3A4. Studies with drugs also metabolized via these pathways—such as carbamazepine, diazepam, glyburide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—did not reveal clinically significant interactions.

An interaction between pantoprazole and other drugs metabolized by the same enzyme system cannot be excluded.

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), nor does it interfere with p-glycoprotein-dependent digoxin absorption.

No interaction has been observed with concomitantly administered antacids.

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

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 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 hepatic impairment should have regular monitoring of liver enzymes, especially during long-term treatment. If liver enzymes increase, treatment with the medicinal product should be discontinued (see section "Dosage and administration").

Concomitant use with NSAIDs.

The use of the medicinal product Topraz, gastro-resistant tablets 20 mg, for prevention of gastric and duodenal ulcers associated with NSAID use should be limited to patients requiring continuous NSAID therapy and who have an increased risk of gastrointestinal complications.

Risk assessment should take into account individual risk factors, including age (>65 years), history of gastric or duodenal ulcers, 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, hematemesis, anaemia, melena), or suspicion of or existing 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. Pantoprazole 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 relevant 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 this medicinal product may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella, 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 over one year. Serious clinical manifestations of hypomagnesaemia, such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia, may develop gradually and initially go unnoticed. 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), patients' conditions improved in most cases after magnesium replacement therapy and discontinuation of PPI treatment.

Patients requiring long-term therapy, or those taking PPIs concurrently with digoxin or medications that may cause hypomagnesaemia (e.g., diuretics), should have serum magnesium levels assessed 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 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 ensure adequate intake of vitamin D and calcium.

Severe cutaneous adverse reactions. 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, patients should seek immediate medical advice, and discontinuation of Topraz 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 CgA level assessment (see section "Pharmacodynamics"). If CgA and gastrin levels have not returned to normal 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.

This medicinal product contains less than 1 mmol (23 mg) of sodium 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 reports on pregnancy outcomes) indicate no embryonal or foeto-neonatal toxicity of the drug. Reproductive toxicity was observed in animal studies. As a precautionary measure, 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 excretion of pantoprazole into human breast milk, but 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 influence reaction rate 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 considered (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 1 hour before a meal, whole, without chewing or crushing, with water.

Recommended Dosage

Adults and children aged 12 years and older

Symptomatic treatment of gastroesophageal reflux disease (GERD).

The recommended dose is 20 mg (1 tablet) of Topraz 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 of the drug once daily, i.e., 1 tablet as needed. A switch to long-term therapy should be considered if adequate symptom control is not achieved with on-demand treatment.

Long-term treatment and prevention of reflux esophagitis relapses.

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

Adults

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

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

Hepatic impairment. In patients with severe hepatic impairment, the dose should not exceed 20 mg (1 tablet) once daily.

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

Elderly patients do not require dose adjustment.

Children. 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 have been 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.

Adverse Reactions

Adverse reactions may be expected in approximately 5% of patients. The most commonly observed adverse reactions are diarrhea and headache (occurring in approximately 1% of patients).

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

For all adverse reactions reported during the post-marketing period, frequency could not 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: 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\textsuperscript{1}, hypokalemia\textsuperscript{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, 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, 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 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\textsuperscript{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.

\textsuperscript{1} Hypocalcemia and/or hypokalemia may be associated with the development of hypomagnesemia (see section "Special precautions for use").

\textsuperscript{2} Muscle spasms as a result of electrolyte imbalance.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product 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. 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.

Aurobindo Pharma Limited - Unit VII / Aurobindo Pharma Limited - Unit VII.
Aurobindo Pharma Ltd, Formulation Unit XV / Aurobindo Pharma Ltd, Formulation Unit XV.

Manufacturer's address and location of operations.

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