Topzol

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

Composition:

Active substance: pantoprazole (pantoprazole);

1 vial contains 40 mg of pantoprazole (as pantoprazole sodium sesquihydrate);

Excipients: edetate disodium, sodium hydroxide (for pH adjustment).

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: lyophilized mass or powder ranging from white to almost white.

Pharmacotherapeutic group.

Drugs for treatment of peptic ulcer and gastroesophageal reflux disease.

ATC Code A02B C02.

Pharmacological properties.

Mechanism of action

Pantoprazole is a substituted benzimidazole that inhibits gastric acid secretion by specifically blocking the proton pumps of parietal cells.

Pantoprazole is transformed into its active form in the acidic environment of parietal cells, where it inhibits the H⁺-K⁺-ATPase enzyme, thus blocking the final step of gastric acid production. Inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, symptoms resolve within 2 weeks. The use of pantoprazole, as well as other proton pump inhibitors (PPIs) and H₂-receptor antagonists, reduces gastric acidity and thereby increases gastrin secretion proportionally to the reduction in acidity. Increased gastrin secretion is reversible. Since pantoprazole binds the enzyme distal to the cellular receptor, it can inhibit gastric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect of oral and intravenous administration of the drug is equivalent.

Pharmacodynamics.

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

Based on animal studies, the influence of long-term (more than 1 year) pantoprazole treatment on thyroid gland endocrine parameters cannot be excluded.

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels rise. Elevated CgA levels may affect diagnostic test results 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, which may be falsely elevated after PPI treatment, to return to the normal range.

Pharmacokinetics.

General pharmacokinetics

Pharmacokinetic properties do not change after single or repeated administration. Within the dose range of 10 to 80 mg, pantoprazole plasma pharmacokinetics 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.

Biotransformation. The substance is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation via CYP2C19, followed by sulfation; other metabolic pathways include oxidation via CYP3A4.

Elimination. The terminal half-life is approximately 1 hour, and clearance is 0.1 L/h/kg. There have been several cases of delayed elimination. 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 action (inhibition of acid secretion).

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, which is conjugated with sulfate. The half-life of the main metabolite (approximately 1.5 hours) slightly exceeds that of pantoprazole.

Special patient groups.

Poor 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 may be primarily catalyzed 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 than in individuals with functionally active CYP2C19 (extensive metabolizers). The mean peak plasma concentration increased by approximately 60%. These findings do not affect pantoprazole dosing.

Renal impairment. No dose adjustment recommendations are required when prescribing pantoprazole to patients with impaired renal function (including dialysis patients). As in healthy volunteers, the half-life of pantoprazole is short. Only very small amounts of pantoprazole are dialyzed. Although the main metabolite has a moderately prolonged half-life (2–3 hours), elimination remains rapid, so accumulation does not occur.

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 single intravenous administration of pantoprazole at doses of 0.8 or 1.6 mg/kg to children aged 2 to 16 years, no significant correlation was observed between pantoprazole clearance and patient age or body weight. AUC and volume of distribution corresponded to data obtained in adult studies.

Clinical characteristics.

Indications.

• Reflux esophagitis.
• Gastric and duodenal ulcer.
• Zollinger–Ellison syndrome and other hypersecretory pathological conditions.

Contraindications.

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

Interaction with other medicinal products and other forms of interactions.

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 of 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 depends on intragastric pH, is not recommended due to a significant reduction in their bioavailability (see section "Special precautions for use").

If 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, increased INR and prolonged prothrombin time have been reported in patients receiving concomitant PPIs and warfarin or phenprocoumon. Increased INR and prolonged prothrombin time may lead to the development of pathological bleeding and even fatal outcomes. Monitoring of INR and prothrombin time is necessary when these drugs are used concomitantly.

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

Other interactions. Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19, with additional metabolic pathways including oxidation by the enzyme CYP3A4. Studies with drugs that are also metabolized via these pathways, such as carbamazepine, diazepam, glyburide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol, did not reveal clinically significant interactions.

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

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 affect P-glycoprotein associated with digoxin absorption.

No interaction has been observed with concurrently administered antacids.

Interaction studies between pantoprazole and certain concurrently 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. 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 testing methods should be considered to confirm results.

Special precautions for use.

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), or suspicion or presence of gastric ulcer, malignancy must be excluded.

If symptoms persist despite adequate treatment, further investigations are required.

Hepatic impairment. Patients with severe hepatic impairment require regular monitoring of liver enzymes. If liver enzymes increase, treatment with the drug must be discontinued (see section "Method of administration and dosage").

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").

Gastrointestinal infections caused by bacteria. Like other proton pump inhibitors, pantoprazole may increase the number of bacteria normally present in the upper gastrointestinal tract. Treatment with the drug may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or C. difficile.

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

Hypomagnesaemia. Cases of severe hypomagnesaemia have been observed in patients treated with PPIs, such as pantoprazole, for at least 3 months, and in most cases for over a year. Serious clinical manifestations of hypomagnesaemia may occur and initially develop insidiously: fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia. In cases of hypomagnesaemia, the condition of patients usually improved after magnesium replacement therapy and discontinuation of PPI treatment.

Patients requiring long-term therapy, or those taking PPIs concomitantly with digoxin or medications that may cause hypomagnesaemia (e.g. diuretics), should have their magnesium levels 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 slightly increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other risk factors. Study results indicate that the use of proton pump inhibitors may increase the overall risk of fractures by 10–40%. Some of these may be attributable to other risk factors. Patients at risk of developing osteoporosis should receive treatment according to current clinical guidelines and should consume adequate amounts of vitamin D and calcium.

Severe cutaneous adverse reactions. Severe skin adverse reactions associated with the use of pantoprazole, which may be life-threatening or lead to fatal outcomes, have been reported, including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis. The frequency of occurrence of these reactions is unknown (see section "Adverse reactions"). Patients should be informed of the signs and symptoms and closely monitored. If symptoms indicating these reactions occur, pantoprazole should be discontinued immediately and alternative treatment 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, particularly in sun-exposed areas, and are accompanied by arthralgia, the patient should seek immediate medical attention, and discontinuation of Topzol should be considered. Development of subacute cutaneous lupus erythematosus in patients during prior treatment with proton pump inhibitors may increase the risk of its occurrence when using other proton pump inhibitors.

Effect on laboratory test results.

Elevated levels of chromogranin A (CgA) may affect test results in the diagnosis of neuroendocrine tumors. To avoid this effect, treatment with Topzol should be temporarily discontinued at least 5 days before assessing CgA levels (see section "Pharmacodynamics"). If CgA and gastrin levels have not returned to the normal range after the initial measurement, repeat measurements should be performed 14 days after discontinuation of proton pump inhibitor therapy.

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 fetotoxic/neonatal 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 discontinue breastfeeding or to discontinue/abstain from treatment with the drug should be made taking into account the benefits of breastfeeding for the child and the benefits of treatment with the drug 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 reaction speed when driving or operating machinery. Possible development of adverse reactions such as dizziness and visual disturbances should be taken into account. In such cases, driving or operating machinery should be avoided.

Administration and Dosage

The drug should be used only as prescribed by a physician and under appropriate medical supervision. Intravenous administration is recommended only when oral administration is not feasible. Data are available on intravenous treatment duration of up to 7 days. Therefore, as soon as oral administration of pantoprazole becomes possible, the transition from intravenous to oral administration should be made at a dose of 40 mg.

Gastroesophageal reflux disease, duodenal ulcer, gastric ulcer

The recommended dose is 40 mg of pantoprazole (1 vial) once daily 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 is 80 mg daily. If necessary, the dose may be titrated up or down depending on gastric acid secretion parameters. Doses exceeding 80 mg daily should be divided into two administrations. A temporary increase in pantoprazole dose to more than 160 mg may be possible, but the duration of use should be limited only to the period required for adequate control of acid secretion.

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

Preparation for use

Reconstitute the drug with 10 mL of 0.9% sodium chloride solution provided in the vial. The reconstituted 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 or reconstitution and dilution, chemical and physical stability for use is maintained for 12 hours at 25 °C.

From a microbiological standpoint, this medicinal product should be used immediately.

If the drug is not used immediately, the responsibility for storage conditions and duration of storage prior to use lies with the user.

The drug must not be prepared or mixed with solvents other than those specified above.

Intravenous administration should be performed over 2–15 minutes.

The vial is intended for single use only. Before use, the drug in the vial should be visually inspected (particularly for color change and presence of precipitate).

The reconstituted solution should be clear and yellowish in color.

Hepatic impairment
In patients with severe hepatic impairment, the daily dose should not exceed 20 mg (½ vial of Topzol, lyophilisate for injection solution, 40 mg) (see section "Special precautions").

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

Elderly patients
Do not require dose adjustment.

Children

The drug is not recommended for use in children (under 18 years of age), as data on safety and efficacy in this age group are limited. Current available data are described in the section "Pharmacokinetics", but dosage recommendations cannot be provided.

Overdose

Symptoms of overdose are unknown.

Doses up to 240 mg administered intravenously over 2 minutes were well tolerated. Since pantoprazole is highly protein-bound, it is not a drug that can be easily removed by dialysis.

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

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

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.

Not known: hyponatremia, hypomagnesemia (see section "Special precautions"), hypocalcemia\textsuperscript{1}, hypokalemia.

Psychiatric disorders.

Uncommon: sleep disorders.

Rare: depression (including exacerbation).

Very rare: disorientation (including exacerbation).

Not known: hallucinations, confusion (particularly in patients predisposed to such disorders, as well as exacerbation of these symptoms if previously 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, bloating, 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\textsuperscript{2}.

Renal and urinary disorders.

Not known: interstitial nephritis (with potential 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 concurrent with hypomagnesemia.
\textsuperscript{2} Muscle spasms as a consequence of electrolyte imbalance.

Shelf life. 2 years.

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

Incompatibilities.

Do not mix with other medicinal products except those specified in the section "Dosage and administration".

Packaging.

Lyophilisate for solution for injection in a vial; 10 vials per carton.

Prescription status. Prescription only.

Manufacturer. Aspiro Pharma Limited.

Manufacturer's address and location of operations.

S.No.321, Biotech park, Phase-III, Karkapatla Village, Markook Mandal, Siddipet Dist-502281, Telangana State, India.