Pantoprotekt

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

Composition:

Active substance: pantoprazole;

1 vial contains pantoprazole 40.0 mg (as pantoprazole sodium sesquihydrate);
Excipients: sodium hydroxide, water for injections.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical characteristics: lyophilized mass of white or almost white color.

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

Pharmacological properties.

Pharmacodynamics. 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 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. 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 thus 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 hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect of oral and intravenous administration of the drug is equivalent.

Pantoprazole treatment increases fasting gastrin levels. With short-term use, these 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 result, prolonged treatment may occasionally lead to mild or moderate increase in specific enterochromaffin-like (ECL) cells in the stomach (similar to adenomatoid hyperplasia). However, according to studies conducted to date, the development of precursor cells of neuroendocrine tumors (atypical hyperplasia) or gastric neuroendocrine tumors, observed in animal studies, has not been observed in humans.

Based on animal study results, a long-term (more than one year) effect of 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. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may affect test results when diagnosing neuroendocrine tumors. Available published data indicate that treatment with proton pump inhibitors should be discontinued for a period of 5 days to 2 weeks prior to measuring CgA levels. This allows CgA levels, which may be falsely elevated after PPI treatment, to return to the normal range.

Pharmacokinetics.

Pharmacokinetic properties do not change 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. The substance is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation by CYP2C19, followed by sulfation; another metabolic pathway involves oxidation by 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 (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 conjugated with sulfate. The half-life of the main metabolite (about 1.5 hours) is only slightly longer than 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 such individuals, pantoprazole metabolism is likely primarily catalyzed by the CYP3A4 enzyme. 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 dosage adjustment recommendations are required when prescribing pantoprazole to patients with impaired renal function (including patients on dialysis). As in healthy volunteers, the half-life of pantoprazole in these patients remains 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 no accumulation occurs.

Hepatic impairment. Although in patients with liver cirrhosis (Child-Pugh classes A and B), the half-life of pantoprazole 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 Cmax observed in elderly volunteers compared to younger volunteers is not clinically significant.

Pediatric patients. 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 relationship was observed between pantoprazole clearance and patient age or body weight. AUC and volume of distribution corresponded to data obtained from adult studies.

Clinical characteristics.

Indications.

• Gastroesophageal reflux disease (reflux esophagitis).
• Duodenal ulcer.
• Gastric ulcer.
• Zollinger-Ellison syndrome and other hypersecretory pathological conditions.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

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

HIV protease inhibitors. Concomitant use of proton pump inhibitors with HIV protease inhibitors whose absorption depends on intragastric pH (such as atazanavir) 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, there have been reports of increased INR and prolonged prothrombin time 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 death. Monitoring of INR and prothrombin time is necessary when these drugs are used concomitantly.

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 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 medicinal products metabolized by the same enzyme system cannot be ruled out.

Results from numerous 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), or affect P-glycoprotein-mediated digoxin absorption.

No interaction was observed with concomitantly administered antacids.

Studies have also been conducted on the interaction of pantoprazole with certain antibiotics when used concomitantly (clarithromycin, metronidazole, amoxicillin). 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 via these enzyme systems.

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

Special precautions for use.

Malignant gastric tumors. Symptomatic response to pantoprazole may mask symptoms of malignant gastric tumors and delay their diagnosis. In the presence of alarm symptoms (e.g., significant weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena), as well as in suspected or confirmed gastric ulcer, malignancy must be ruled out. If symptoms persist despite adequate treatment, further investigations are required.

Hepatic impairment. In patients with severe hepatic impairment, liver enzyme levels should be monitored regularly. If liver enzymes are elevated, pantoprazole treatment must 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").

Gastrointestinal infections caused by bacteria. Pantoprazole treatment may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile.

Hypomagnesemia. Rare cases of severe hypomagnesemia have been reported in patients treated with proton pump inhibitors (PPIs), including pantoprazole, for at least three months, and mostly within a year. Serious clinical manifestations of hypomagnesemia, which may initially be subtle, include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia. Hypomagnesemia may lead to the development of hypocalcemia and/or hypokalemia (see section "Undesirable effects"). In cases of hypomagnesemia (and associated hypocalcemia and/or hypokalemia), the condition of most patients improved after corrective therapy with magnesium supplements and discontinuation of PPI treatment. In patients requiring long-term therapy, and in those receiving PPIs concomitantly with digoxin or other medicinal products that may cause hypomagnesemia (e.g., diuretics), serum magnesium levels should be measured before starting PPI therapy and periodically during treatment.

Bone fractures. Long-term (more than 1 year) high-dose treatment with proton pump inhibitors increases the risk of fractures of the hip, wrist, and spine, particularly in elderly patients or those with 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 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, including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with pantoprazole at an unknown frequency. These reactions may be life-threatening or fatal (see section "Undesirable effects").

Patients should be informed about the signs and symptoms of severe cutaneous adverse reactions and advised to monitor closely for skin manifestations.

If signs or symptoms suggestive of these reactions occur, pantoprazole should be discontinued immediately and alternative therapy 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 Pantoprotec should be considered. Development of subacute cutaneous lupus erythematosus during previous treatment with proton pump inhibitors increases the risk of recurrence with other proton pump inhibitors.

Effect on laboratory test results. Elevated chromogranin A (CgA) levels may interfere with diagnostic testing for neuroendocrine tumors. To avoid this interference, Pantoprotec treatment should be temporarily discontinued at least 5 days before assessing CgA levels (see section "Pharmacodynamics"). If CgA and gastrin levels have not returned to normal range after initial measurement, repeat measurements should be performed 14 days after discontinuation of proton pump inhibitor therapy.

Important information on excipients.

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

Use during pregnancy or breastfeeding.

Pregnancy. Available data on the use of pantoprazole in pregnant women (approximately 300–1000 pregnancy outcomes reported) indicate no evidence of teratogenic or fetal/neonatal toxicity. Reproductive toxicity was observed in animal studies. As a precautionary measure, Pantoprotec should be avoided during pregnancy.

Breastfeeding. Animal studies have shown excretion of pantoprazole into breast milk. Data on excretion of pantoprazole into human breast milk are limited, but such excretion has been reported. A risk to newborns/infants cannot be excluded. The decision to discontinue breastfeeding or to discontinue/abstain from Pantoprotec therapy should be made taking into account the benefits of breastfeeding for the child and the benefits of therapy 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. However, the possibility of adverse reactions such as dizziness and visual disturbances should be considered (see section "Undesirable effects"). In such cases, driving or operating machinery should be avoided.

Method of Administration and Dosage

The medicinal product should be used 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, intravenous administration of Pantoprotekt should be discontinued and oral pantoprazole at a dose of 40 mg should be initiated.

Gastroesophageal reflux disease, duodenal ulcer, gastric ulcer.

The recommended dose is 40 mg of pantoprazole (1 vial) 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 of Pantoprotekt is 80 mg daily. If necessary, the dose may be titrated upwards or downwards depending on gastric acid secretion parameters. Doses exceeding 80 mg daily should be divided into two administrations. A temporary increase in pantoprazole dose above 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 reduction of acidity 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.

The powder should be dissolved 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 medicinal product is maintained for 12 hours at 25 °C. From a microbiological standpoint, the diluted solution should be used immediately.

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

Intravenous administration of the medicinal product should be performed over 2–15 minutes. The vial is intended for single use only. Any unused portion of the product or product with altered physicochemical properties (e.g. color change, precipitation) must be discarded according to local regulations. The diluted solution should be a clear yellowish liquid.

Hepatic impairment. In patients with severe hepatic impairment, the daily dose should not exceed 20 mg (0.5 vial of Pantoprotekt) (see section "Special precautions").

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

Elderly patients do not require dose adjustment.

Children.

Pantoprotekt is not recommended for use in children (under 18 years of age) due to limited data on safety and efficacy in this age group.

Current available data are presented in the section "Pharmacokinetics", however, dosage recommendations cannot be provided.

Overdose.

Symptoms. Symptoms of overdose are unknown.

Doses up to 240 mg administered intravenously over 2 minutes were well tolerated.
Treatment. Since pantoprazole is extensively 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 recommendations for specific antidotal therapy.

Side effects.

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.

Adverse 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), unknown (frequency cannot be estimated from available data). For all adverse reactions reported during the post-marketing period, frequency cannot be determined; therefore, they are listed as "unknown".

Within each frequency category, adverse reactions are listed in order of decreasing severity.

Blood and lymphatic system disorders.

Rare: agranulocytosis.

Very rare: leukopenia, thrombocytopenia, pancytopenia.

Immune system disorders.

Rare: hypersensitivity reactions (including anaphylactic reactions, anaphylactic shock).

Metabolism and nutrition disorders.

Rare: hyperlipidemia and increased lipid levels (triglycerides, cholesterol), changes in body weight.

Unknown: hyponatremia, hypomagnesemia (see section "Special precautions"), hypocalcemia^1, hypokalemia^1.

Psychiatric disorders.

Uncommon: sleep disorders.

Rare: depression (including exacerbation).

Very rare: disorientation (including exacerbation).

Unknown: hallucination, 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.

Unknown: paresthesia.

Eye disorders.

Rare: visual disturbances / blurred vision.

Gastrointestinal disorders.

Common: fundic gland polyps (benign).

Uncommon: diarrhea, nausea, vomiting, flatulence, 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, toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme, drug reaction with eosinophilia and systemic symptoms (DRESS), 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.

Unknown: muscle spasms^2.

Renal and urinary disorders.

Unknown: tubulointerstitial nephritis (with possible progression to 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.

^1 Hypocalcemia and/or hypokalemia may be associated with the development of hypomagnesemia (see section "Special precautions").

^2 Muscle spasms as a consequence of electrolyte imbalance.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization of a medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25°C, protected from light and out of reach of children.

Packaging.

40 mg of lyophilisate in a vial. 1 vial in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

VEM Ilac San. ve Tic. A.S.

Manufacturer's address and location of operations.

Cerkezkoy Organize Sanayi Bölgesi, Karagac Mahallesi, Fatih Boulevard No:38, Kapakli / Tekirdag / Turkey