Topraz

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

Composition:

Active substance: pantoprazole;

One vial contains pantoprazole sodium sesquihydrate equivalent to 40.0 mg of pantoprazole.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: lyophilized porous mass or powder, white or almost white, placed in a clear glass vial, stoppered with a grey rubber stopper, sealed with an aluminum cap with a blue polypropylene disc.

The reconstituted solution is a clear solution ranging from colorless to yellowish.

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

Pharmacological Properties

Pharmacodynamics

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 acid production. Inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. Most patients become symptom-free within 2 weeks. The use of pantoprazole, as with 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 to the enzyme distal to the cellular receptor, it can inhibit gastric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is equivalent following oral and intravenous administration.

Administration of pantoprazole increases fasting gastrin levels. With short-term use, gastrin levels usually do not exceed the upper limit of normal. With long-term treatment, gastrin levels typically double. Excessive increases, however, occur only in isolated cases. As a result, a slight or moderate increase in the number of enterochromaffin-like (ECL) cells in the stomach (similar to adenomatoid hyperplasia) may occur in a small number of cases during prolonged therapy. However, according to available studies, the development of precursor cells for neuroendocrine tumors (atypical hyperplasia) or gastric neuroendocrine tumors, observed in animal experiments, 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. Chromogranin A (CgA) levels also increase due to reduced gastric juice acidity. Elevated CgA levels may interfere with the diagnosis of neuroendocrine tumors.

Available published data indicate that proton pump inhibitor therapy should be discontinued for a period of 5 days to 2 weeks before measuring CgA levels. This is necessary to allow CgA levels, which may be elevated due to PPI therapy, to return to the baseline range.

Pharmacokinetics

Absorption. Pharmacokinetic properties remain unchanged after single or repeated administration. In the dose range of 10 to 80 mg, the plasma pharmacokinetics of pantoprazole remain linear both after oral administration and intravenous infusion.

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

Biological transformation. Pantoprazole is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation via CYP2C19, followed by sulfate conjugation; another metabolic pathway involves oxidation via CYP3A4.

Elimination. The terminal half-life 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, the half-life does not correlate with the much longer duration of action (acid secretion inhibition).

The majority of pantoprazole metabolites are excreted in urine (approximately 80%), with the remainder eliminated in feces. The main metabolite in both serum and urine is desmethylpantoprazole sulfate conjugate. The half-life of the main metabolite (about 1.5 hours) is slightly longer than that of pantoprazole.

Special patient groups

Poor metabolizers. Approximately 3% of Europeans have low functional activity of the CYP2C19 enzyme and are referred to as poor metabolizers. In these individuals, pantoprazole metabolism is likely catalyzed primarily by CYP3A4. After a single 40 mg dose of pantoprazole, the mean area under the plasma concentration-time curve (AUC) was approximately 6 times higher in poor metabolizers compared to individuals with functionally active CYP2C19 (extensive metabolizers). The mean peak plasma concentration increased by about 60%. These findings do not affect pantoprazole dosing recommendations.

Renal impairment. No dosage adjustment is recommended for pantoprazole in patients with impaired renal function (including dialysis patients). As in healthy individuals, the half-life of pantoprazole remains short. Only minimal 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 half-life increases to 7–9 hours and AUC increases 5–7 times, the maximum serum concentration increases only slightly—by 1.5 times—compared to healthy volunteers.

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

Children. After a single intravenous dose of pantoprazole at 0.8 or 1.6 mg/kg in children aged 2 to 16 years, no significant relationship was observed between pantoprazole clearance and patient age or body weight. AUC and volume of distribution were consistent with data obtained from adult studies.

Clinical characteristics.

Indications.

TOPRAZ is indicated for use in adults for:

• gastroesophageal reflux disease (GERD),
• gastric and duodenal ulcers,
• Zollinger-Ellison syndrome and other hypersecretory conditions.

Contraindications. Hypersensitivity to the active substance or to benzimidazole derivatives.

Interaction with other medicinal products and other forms of interaction.

Medicinal products whose absorption is pH-dependent. Due to complete and prolonged inhibition of gastric acid secretion, pantoprazole may affect the absorption of drugs for which gastric pH is an important factor in their bioavailability (e.g., certain 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").

In cases where concomitant use of HIV protease inhibitors with proton pump inhibitors 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, there have been reports of increased INR and prolonged prothrombin time in patients receiving PPIs and warfarin or phenprocoumon concurrently. Increased INR and prolonged prothrombin time may lead to clinically significant bleeding and even death. When these drugs are used concomitantly, monitoring of INR and prothrombin time is necessary.

Methotrexate. There have been reports that concomitant administration of high-dose methotrexate (e.g., 300 mg) and proton pump inhibitors increases methotrexate blood levels in some patients. Patients receiving high-dose methotrexate, such as those with cancer or psoriasis, should temporarily discontinue pantoprazole therapy.

Other interactions. Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19; other metabolic pathways include oxidation by CYP3A4. Studies with drugs that are also metabolized through these pathways, such as carbamazepine, diazepam, glyburide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol, have not shown clinically significant interactions. Interaction between pantoprazole and other drugs metabolized by 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), CYP2E1 (e.g., ethanol), nor does it interfere with P-glycoprotein-dependent digoxin absorption.

No interaction has been observed with concomitantly administered antacids.

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

Medicinal products that inhibit or induce CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, may increase the systemic exposure to pantoprazole. Consideration should be given to reducing the dose in patients receiving long-term, high-dose pantoprazole therapy and in patients with impaired liver function. Enzyme inducers affecting CYP2C19 and CYP3A4, such as rifampicin and St. John's wort (Hypericum perforatum), may reduce plasma concentrations of PPIs metabolized by these enzyme systems.

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

Special precautions for use.

Gastric malignancies. Systematic response to pantoprazole treatment may mask symptoms of gastric malignancies and delay their diagnosis. In the presence of any alarming symptoms (e.g., significant weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena), as well as in suspected or confirmed gastric ulcer, malignancy must be excluded, since treatment with pantoprazole may mask symptoms and delay diagnosis. If symptoms persist despite adequate therapy, further investigations are required.

Hepatic impairment. In patients with severe hepatic impairment, liver enzymes should be monitored regularly. If liver enzymes increase, treatment with the drug should be discontinued (see section "Dosage and administration").

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").

The dose of pantoprazole should not exceed 20 mg per day.

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

Sodium. The medicinal product contains less than 1 mmol of sodium (23 mg) per vial, i.e., it is essentially "sodium-free".

Hypomagnesemia. Rare cases of severe hypomagnesemia have been reported in patients treated with proton pump inhibitors (PPIs), such as pantoprazole, for at least three months, and in most cases, after one year. Hypomagnesemia may develop insidiously and lead to serious clinical manifestations such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia. Hypomagnesemia may lead to the development of hypocalcemia and/or hypokalemia (see section "Adverse reactions"). In cases of hypomagnesemia (and associated hypocalcemia and/or hypokalemia), the condition of most patients improved after magnesium replacement therapy and discontinuation of PPI treatment.

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

Bone fractures. Long-term treatment (more than 1 year) with high doses of proton pump inhibitors may moderately 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 indicate that the use of proton pump inhibitors increases the overall risk of fractures by 10–40%. Some of these fractures may be attributable to other risk factors. Patients at risk of developing osteoporosis should receive treatment according to current clinical guidelines and should ensure adequate intake of vitamin D and calcium.

Severe cutaneous adverse reactions. Severe cutaneous adverse reactions associated with the use of pantoprazole, 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 should be closely monitored for their development. If signs or symptoms suggestive of these reactions occur, pantoprazole should be discontinued immediately and alternative therapy should be considered.

Subacute cutaneous lupus erythematosus. The use of proton pump inhibitors 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 Topraz should be considered. Development of subacute cutaneous lupus erythematosus in patients during previous therapy with proton pump inhibitors increases the risk of its recurrence with other proton pump inhibitors.

Effect on laboratory test results. Elevated chromogranin A (CgA) levels may interfere with neuroendocrine tumor assessments. To avoid such interference, Topraz treatment should be suspended at least 5 days before measuring CgA levels (see section "Pharmacological properties"). If CgA and gastrin levels do not return to the reference range after initial measurements, the test should be repeated 14 days after discontinuation of proton pump inhibitor therapy.

Use during pregnancy or breastfeeding.

Pregnancy. Available data on the use of pantoprazole in pregnant women (approximately 300–1000 pregnancy outcome reports) indicate no evidence of embryotoxic or fetotoxic/neonatal toxicity. Reproductive toxicity was observed in animal studies. Pregnant women should avoid the use of pantoprazole.

Breastfeeding. Animal studies have shown excretion of pantoprazole into breast milk. There is insufficient data on 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 only 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.

Administration and Dosage

The medicinal product is intended for use in adults as prescribed and under direct medical supervision.

Intravenous administration of the drug is recommended only when oral administration is not possible. Data are available on intravenous treatment duration of up to 7 days. When clinically feasible, a switch from intravenous administration of Topraz to oral pantoprazole at a dose of 40 mg should be implemented.

Gastroesophageal reflux disease, duodenal ulcer, gastric ulcer.

The recommended dose is 40 mg of pantoprazole (1 vial) per day administered intravenously.
Treatment of Zollinger–Ellison syndrome and other hypersecretory conditions.

For long-term treatment of Zollinger–Ellison syndrome and other hypersecretory conditions, the recommended initial dose of the medicinal product Topraz is 80 mg per day. If necessary, the dose may be titrated upward or downward depending on gastric acid secretion parameters. Doses exceeding 80 mg per day should be divided into two administrations. A temporary increase in the pantoprazole dose to more than 160 mg may be considered, but the duration of such treatment should be limited to the period required for adequate control of acid secretion.

If rapid acid reduction is required, an initial dose of 2 × 80 mg is sufficient for most patients to achieve the desired level (< 10 mEq/h) within 1 hour.

Preparation for use.

Dissolve the powder in 10 mL of 0.9% sodium chloride solution provided in the vial. The solution may be administered directly or after dilution with 100 mL of 0.9% sodium chloride solution or 5% glucose solution in plastic or glass infusion bottles. After reconstitution, the chemical and physical stability of the drug is maintained for 12 hours at 25 °C. From a microbiological standpoint, the diluted solution should be used immediately.

Topraz must not be prepared or mixed with solvents other than those specified above. The intravenous infusion should be administered over 2–15 minutes. The vial is intended for single use only. Before administration, vials should be visually inspected, particularly for color changes and presence of precipitate.

The reconstituted solution should be clear, colorless or slightly yellow. Any unused portion or any solution with altered physicochemical properties (e.g. color change, precipitate formation) must be discarded according to local regulations.

Hepatic impairment. In patients with severe hepatic impairment, the daily dose should not exceed 20 mg (½ vial of Topraz 40 mg powder).

Renal impairment. Patients with impaired renal function do not require dose adjustment.

Elderly patients do not require dose adjustment.

Pediatric population. Topraz, powder for injection solution, is not recommended for use in children (under 18 years of age) due to limited data on safety and efficacy in this age group.

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 readily dialyzable.

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

Adverse Reactions

Adverse reactions may be expected in approximately 5% of patients. The most common adverse reaction is thrombophlebitis at the injection site. Diarrhea and headache occurred in about 1% of patients.

Undesirable effects are classified by frequency of occurrence into the following categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), unknown (frequency cannot be estimated from available data).

For all adverse reactions reported during the post-marketing period, it is not possible to determine a frequency; therefore, they are listed as "unknown".

Within each frequency group, adverse reactions are presented 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), changes in body weight.

Unknown: 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: confusion (including exacerbation).

Unknown: hallucination, confusion (especially in patients predisposed to such disorders, and including exacerbation of these symptoms if already present).

Nervous system disorders.

Uncommon: headache, dizziness.

Rare: taste disturbances.

Unknown: paraesthesia.

Eye disorders.

Rare: visual disturbances / blurred vision.

Gastrointestinal disorders.

Common: fundic gland polyps (benign).

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

Unknown: microscopic colitis.

Hepatobiliary disorders.

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

Rare: increased bilirubin levels.

Unknown: hepatocellular injury, jaundice, hepatocellular failure.

Skin and subcutaneous tissue disorders.

Uncommon: skin rashes, exanthema, pruritus.

Rare: urticaria, angioneurotic edema.

Unknown: Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special precautions for use").

Musculoskeletal and connective tissue disorders.

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

Rare: arthralgia, myalgia.

Unknown: muscle spasms\textsuperscript{2}.

Renal and urinary disorders.

Unknown: tubulointerstitial nephritis (with possible development of renal failure).

Reproductive system and breast disorders.

Rare: gynecomastia.

General disorders.

Common: thrombophlebitis at the injection site.

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 of 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 the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

From a microbiological standpoint, the reconstituted preparation should be used immediately. However, the physico-chemical stability of the reconstituted preparation is maintained for 12 hours at 25 °C.

Storage conditions. Store in the original packaging to protect from light at a temperature not exceeding 25 °C. Keep out of reach and sight of children.

Incompatibilities. The medicinal product Topraz should not be mixed with other medicinal products except those specified in the section "Administration and dosage".

Packaging. Powder for solution for injection in a vial. 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Eugia Pharma Specialities Limited, Unit-III

Manufacturer's address and location of operation.

Plot No`s: 4, 34 to 48, EPZ, TSIIC, IDA, Pashamylaram Village, Patancheru Mandal, Sanga Reddy District, Telangana state, 502307, India.