Pantoprazole

INSTRUCTION for medical use of the medicinal product Pantoprazole (Pantoprazole)

Composition:

active substance: pantoprazole;

1 vial contains 45.1 mg of pantoprazole sodium sesquihydrate equivalent to 40 mg of pantoprazole;

excipients: disodium edetate, sodium hydroxide.

Pharmaceutical form. Powder for solution for injection.

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

Pharmacotherapeutic group.

Medicinal products for the treatment of acid-related disorders. Proton pump inhibitors. Pantoprazole.

ATC code A02BC02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Pantoprazole is a substituted benzimidazole that inhibits gastric hydrochloric acid secretion by specifically blocking proton pumps in 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 hydrochloric acid production in the stomach. 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 with other proton pump inhibitors (PPIs) and H2-receptor antagonists, reduces gastric acidity and consequently 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 acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same following oral or intravenous administration.

Pantoprazole use increases fasting gastrin levels. With short-term use, levels usually remain within the upper limit of normal. With long-term treatment, gastrin levels typically double. Marked elevation occurs only in isolated cases. As a consequence, mild or moderate increase in specific enterochromaffin-like (ECL) cells in the stomach (similar to adenomatoid hyperplasia) may occasionally be observed during prolonged treatment. However, according to studies conducted to date, development of precursor cells of neuroendocrine tumors (atypical hyperplasia) or gastric neuroendocrine tumors, which were observed in animal studies, has not been observed in humans.

Based on animal study results, a potential effect of long-term (more than one year) pantoprazole treatment on thyroid gland endocrine parameters cannot be completely ruled out.

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels rise. Elevated CgA levels may interfere with diagnostic 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, 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. Within the dose range of 10 mg to 80 mg, the pharmacokinetics of pantoprazole in plasma remain linear, both after oral administration and intravenous infusion.

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

Biological transformation. The substance is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation via CYP2C19, followed by sulfation; other metabolic pathways include 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 reported. 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 (acid secretion inhibition).

The majority of pantoprazole metabolites are excreted in urine (approximately 80%), the remainder in feces. The main metabolite in both plasma and urine is desmethylpantoprazole sulfate conjugate. The half-life of the main metabolite (approximately 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 and 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 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 maximum plasma concentration increased by approximately 60%. These findings do not affect pantoprazole dosing.

Renal impairment. No dosage adjustment is recommended for pantoprazole in patients with impaired renal function (including patients on dialysis). As in healthy volunteers, the elimination half-life of pantoprazole 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, and thus 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 (Cmax) increases only slightly—by 1.5 times—compared to healthy volunteers.

Elderly patients. A slight increase in AUC and Cmax in elderly volunteers compared to younger volunteers has no clinical significance.

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

Clinical characteristics.

Indications.

• Gastroesophageal reflux disease (GERD).
• Gastric and duodenal ulcers.
• Zollinger-Ellison syndrome and other hypersecretory conditions.

Contraindications.

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

Interaction with other medicinal products and other forms of interactions.

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 antifungal agents such as ketoconazole, itraconazole, posaconazole, or other drugs such as erlotinib).

HIV protease inhibitors. Concomitant use of pantoprazole with HIV protease inhibitors (e.g., atazanavir), whose absorption is pH-dependent, 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 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 the international normalized ratio (INR). However, increased INR and prolonged prothrombin time have been reported in patients receiving PPIs together with warfarin or phenprocoumon. Elevated INR and prolonged prothrombin time may lead to pathological bleeding and even fatal outcomes. Monitoring of INR and prothrombin time is necessary when these drugs are used concomitantly.

Methotrexate. There have been reports of increased blood levels of methotrexate when high-dose methotrexate (e.g., 300 mg) is administered concomitantly with PPIs 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 drugs metabolized via the same enzyme system cannot be excluded.

Results from several studies on potential interactions indicate that pantoprazole does not affect the metabolism of substances metabolized by CYP1A2 (e.g., caffeine, theophylline), CYP2C9 (e.g., piroxicam, diclofenac, naproxen), CYP2D6 (e.g., metoprolol), or CYP2E1 (e.g., ethanol). It also does not affect P-glycoprotein, which is associated with digoxin absorption.

No interaction was observed with concomitantly administered antacids.

Studies on the interaction between pantoprazole and certain concomitantly administered antibiotics (clarithromycin, metronidazole, amoxicillin) have also 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 urine screening tests for tetrahydrocannabinol (THC) have been reported in patients taking pantoprazole. Alternative confirmatory testing methods should be considered to verify positive results.

Special precautions for use.

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 cases of suspected or confirmed gastric ulcer, malignancy must be ruled out.

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 "Dosage and administration").

HIV protease inhibitors. Concomitant use of pantoprazole with HIV protease inhibitors (e.g., 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. Treatment with pantoprazole may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile.

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

Hypomagnesemia. Cases of severe hypomagnesemia have been observed in patients treated with proton pump inhibitors (PPIs), such as pantoprazole, for at least three months, and in most cases, after one year of treatment. Serious clinical manifestations of hypomagnesemia, which may develop insidiously, include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias.

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.

Patients requiring long-term therapy, or those taking PPIs concomitantly with digoxin or medications that may cause hypomagnesemia (e.g., diuretics), should have their magnesium levels measured before starting PPI treatment and periodically during treatment.

Bone fractures. Long-term (more than 1 year) high-dose PPI treatment may moderately increase the risk of fractures of the hip, wrist, and spine, particularly in elderly patients or those with other risk factors.

Observational studies indicate that PPI use may increase the overall risk of fractures 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 (see section "Adverse reactions"), potentially life-threatening or fatal, such as erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported. Patients should be informed about the signs and symptoms of these skin reactions, and careful monitoring for their development is essential. 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 PPIs has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions develop, particularly in sun-exposed areas, and are accompanied by arthralgia, patients should seek immediate medical advice, and discontinuation of pantoprazole 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 tumors. To avoid this interference, pantoprazole treatment should be temporarily discontinued at least 5 days before CgA assessment (see section "Pharmacodynamics"). If CgA and gastrin levels have not returned to normal range after initial measurement, repeat measurements should be performed 14 days after discontinuation of PPI treatment.

Use during pregnancy or breastfeeding.

Pregnancy. Available data on the use of pantoprazole in pregnant women (approximately 300–1000 pregnancy outcomes reported) indicate no embryonal or fetal/neonatal toxicity. Reproductive toxicity was observed in animal studies. As a precautionary measure, pantoprazole 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. Risk to newborns/infants cannot be excluded. A decision on whether to discontinue breastfeeding or to discontinue/abstain from pantoprazole treatment should be made, taking into account the benefits of breastfeeding for the child and the benefits of pantoprazole treatment for the woman.

Fertility. Pantoprazole did not impair fertility in animal studies.

Ability to drive and use machines.

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

Method of Administration and Dosage

The medication should be used as prescribed by a physician and under appropriate medical supervision.

Intravenous administration of the drug 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, transition should be made from intravenous administration of Pantoprazole to oral pantoprazole at a dose of 40 mg.

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 Pantoprazole is 80 mg daily. The dose may be titrated upward or downward as necessary, depending on gastric acid secretion parameters. Doses exceeding 80 mg daily should be divided into two administrations. Temporary dose increases of pantoprazole to more than 160 mg may be possible, but 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/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 reconstituted solution should be clear and yellowish. 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 bags.

After reconstitution or reconstitution and dilution, the chemical and physical stability of the medication is maintained for 24 hours at 25 °C. From a microbiological standpoint, the medication should be used immediately.

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

Intravenous administration of the medication should be performed over 2–15 minutes.

The vial is intended for single use only. Any unused portion of the medication or medication with altered physicochemical properties (e.g. change in color, presence of precipitate) must be discarded in accordance with local regulations.

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

Pantoprazole, powder for injection solution, is not recommended for use in children (under 18 years of age), as data on safety and efficacy in this age group are limited. Available data are described in the "Pharmacokinetics" section; however, 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 is 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.

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 approximately 1% of patients.

Adverse reactions 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), frequency not known (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 "frequency not known".

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.

Frequency not known: hyponatremia, hypomagnesemia (see section "Special precautions for use"), hypocalcemia^1, hypokalemia^1.

Psychiatric disorders

Uncommon: sleep disorders.

Rare: depression (including exacerbation).

Very rare: confusion (including exacerbation).

Frequency not known: hallucinations, confusion (particularly in patients predisposed to such disorders, and including exacerbation of these symptoms if previously present).

Nervous system disorders

Uncommon: headache, dizziness.

Rare: taste disturbances.

Frequency not known: paraesthesia.

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.

Frequency not known: microscopic colitis.

Hepatobiliary disorders

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

Rare: increased bilirubin levels.

Frequency not known: hepatocellular injury, jaundice, hepatocellular failure.

Skin and subcutaneous tissue disorders

Uncommon: skin rashes, exanthema, pruritus.

Rare: urticaria, angioneurotic edema.

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

Musculoskeletal and connective tissue disorders

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

Rare: arthralgia, myalgia.

Frequency not known: muscle spasms^2.

Renal and urinary disorders

Frequency not known: 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.

^1 Hypocalcemia and/or hypokalemia may be associated with the development of hypomagnesemia.

^2 Muscle spasms as a consequence of electrolyte imbalance.

Reporting of 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, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging, protected from light, at a temperature not exceeding 25 °C.

Keep out of reach of children.

Detailed storage recommendations for the medicinal product

From a microbiological standpoint, the reconstituted or reconstituted and diluted solution should be used immediately. However, the physico-chemical stability of the reconstituted or reconstituted and diluted solution is maintained for 24 hours at a temperature of (25 °C ± 2 °C).

Incompatibilities.

This medicinal product must not be mixed with other medicinal products except those specified in the section "Administration and dosage".

Packaging.

40 mg in a glass vial, stoppered with a rubber stopper and sealed with an aluminum crimp cap equipped with a flip-off cap providing a tamper-evident seal.

1 vial per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

Hainan Poly Pharm Co., Ltd.

Manufacturer's address and location of operations.

Guilinyan Economic Development Area, Meilan District, Haikou, Hainan 571127, China.