Pantasane

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PANTASUN (PANTASUN)

Composition:

Active substance: pantoprazole;

1 vial contains pantoprazole sodium sesquihydrate equivalent to pantoprazole 40 mg.

Pharmaceutical form. Lyophilisate powder for preparation of solution for injection|administration|.

Main physicochemical properties: lyophilisate mass of white or almost white color.

Pharmacotherapeutic group.

Agents for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. ATC code A02BC02.

Pharmacological properties.

Pharmacodynamics.

Pantoprazole, the active substance of the medicinal product, inhibits gastric hydrochloric acid secretion by specifically acting on the proton pump of parietal cells.

Pantoprazole is converted into its active form in an acidic environment, specifically within the parietal cells of the stomach, where it inhibits H+/K+-ATPase, the final step in hydrochloric acid production, regardless of the nature of the stimulant promoting acid secretion. The inhibition is dose-dependent and affects both basal and stimulated gastric acid secretion. Treatment with pantoprazole reduces gastric acidity, leading to a proportional increase in gastrin secretion. The increase in gastrin levels is reversible. Since pantoprazole binds to enzymes located away from cellular receptors, it inhibits hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same following oral or intravenous administration.

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 increases occur only rarely. As a consequence, prolonged therapy may occasionally lead to mild or moderate increase in specific enterochromaffin-like (ECL) cells in the stomach (similar to adenomatoid hyperplasia). However, according to available studies, the development of precursor cells of neuroendocrine tumors (atypical hyperplasia) or gastric neuroendocrine tumors, observed in animal studies, has not been reported in humans.

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

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels rise. Elevated CgA levels may interfere with diagnostic testing for neuroendocrine tumors. Published data indicate that proton pump inhibitor (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 therapy, to return to the normal range.

Pharmacokinetics.

The volume of distribution is 0.15 L/kg, and clearance is approximately 0.1 L/h/kg. The elimination half-life is 1 hour. Due to the specific activation of pantoprazole in parietal cells, the elimination half-life does not correlate with the duration of effect (acid secretion inhibition).

Pharmacokinetics are not altered after single or repeated administration. Within the dose range of 10 to 80 mg, the pharmacokinetics of pantoprazole remain linear both after oral administration and intravenous injection.

Plasma protein binding of pantoprazole is 98%.

The drug is metabolized in the liver. The primary route of metabolite elimination is renal (approximately 80%), with 20% excreted in feces. The main metabolite in both plasma and urine is desmethylpantoprazole sulfate. The elimination half-life of the main metabolite (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, 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 approximately 60%. These findings do not affect pantoprazole dosing.

Renal impairment. No dose reduction is recommended when prescribing pantoprazole to patients with impaired renal function, including those on dialysis. As in healthy individuals, the elimination half-life of pantoprazole in these patients is short. Only very small amounts of pantoprazole are dialyzed. Although the half-life of the main metabolite is slightly prolonged (2–3 hours), it is rapidly eliminated and does not accumulate.

Hepatic impairment. Although in patients with liver cirrhosis (Child-Pugh classes A and B) the elimination half-life of the active substance increases to 7–9 hours, and the area under the concentration-time curve (AUC) correspondingly increases, the maximum plasma concentration (Cmax) of pantoprazole increases only 1.5-fold compared to healthy subjects.

Elderly patients. The slight increase in AUC and Cmax observed in elderly patients compared to younger patients 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 relationship 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.

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

Contraindications.

Hypersensitivity to the active substance, as well as to benzimidazole derivatives.

Interaction with other medicinal products and other types of interactions.

Effect of pantoprazole on the absorption of other drugs.

Drugs whose absorption is pH-dependent. Due to complete and prolonged inhibition of hydrochloric 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 (such as atazanavir), whose absorption is dependent on intragastric pH, is not recommended due to a significant reduction in their bioavailability (see section "Special warnings and precautions for use").

If concomitant use of HIV protease inhibitors with 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 administration 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 required when these drugs are used concomitantly.

Methotrexate. Concomitant use of PPIs with high doses of methotrexate (e.g., 300 mg) may increase and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, potentially leading to toxicity. 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 CYP3A4. Studies with drugs that are also metabolized via these pathways—such as carbamazepine, diazepam, glyburide, nifedipine, phenprocoumon, and oral contraceptives containing levonorgestrel and ethinylestradiol—did not reveal clinically significant interactions.

Interaction with other drugs metabolized via the same enzyme system cannot be ruled out.

Results from interaction studies indicate that pantoprazole does not affect the metabolism of active substances metabolized by CYP1A2 (e.g., caffeine, theophylline), CYP2C9 (e.g., piroxicam, diclofenac, naproxen), CYP2D6 (e.g., metoprolol), or CYP2E1 (e.g., ethanol). It does not affect P-glycoprotein, which mediates digoxin absorption. No interaction was observed with concomitantly administered antacids.

When studying the interaction of pantoprazole with concomitantly administered certain antibiotics (clarithromycin, metronidazole, amoxicillin), no clinically significant interactions were observed.

Drugs 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, as well as 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.

Effect of medicinal products on laboratory test results. False-positive results in certain 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 neoplasms. 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), as well as in suspected or confirmed gastric ulcer, malignancy must be excluded.

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

Hepatic impairment. In patients with severe hepatic dysfunction, liver enzymes should be monitored regularly. If liver enzymes increase, treatment with the drug should be discontinued.

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, 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 and 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), including pantoprazole, for at least 3 months, in most cases after 1 year of treatment. Hypomagnesemia may develop insidiously and manifest as serious clinical symptoms such as 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), patients' conditions generally improved after magnesium replacement therapy and discontinuation of PPIs.

Patients requiring long-term therapy or those receiving PPIs in combination with digoxin or medications that may cause hypomagnesemia (e.g., diuretics) should have serum magnesium levels measured before initiating PPI treatment and periodically during treatment.

Bone fractures. Long-term treatment (more than 1 year) with high doses of proton pump inhibitors is associated with a slightly increased risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other risk factors. According to some data, 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 appropriate treatment according to current clinical guidelines and ensure adequate intake of vitamin D and calcium.

Severe cutaneous adverse reactions. Serious, potentially life-threatening or fatal cutaneous adverse reactions of unknown frequency associated with pantoprazole use have been reported (see section "Adverse reactions"), including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Patients should be informed about the signs and symptoms of these skin reactions and closely monitored for their development. If signs or symptoms suggestive of these reactions occur, pantoprazole should be discontinued immediately and alternative 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 pantoprazole should be considered. Previous development of subacute cutaneous lupus erythematosus during treatment with proton pump inhibitors may increase the risk of recurrence with other PPIs.

Effect on laboratory test results.

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

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 embryotoxic or fetotoxic/neonatal toxicity. Reproductive toxicity was observed in animal studies. As a precautionary measure, pantoprazole should be avoided during pregnancy.

Breastfeeding. Data are available on the excretion of pantoprazole in breast milk. Risk to newborns/infants cannot be excluded. The decision to discontinue breastfeeding or to discontinue/abstain from Pantasan treatment should be made considering the benefits of breastfeeding for the child and the benefits of pantoprazole therapy for the mother.

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 occurrence of adverse reactions such as dizziness and visual disturbances should be taken into account. In such cases, patients should refrain from driving or operating machinery.

Method of Administration and Dosage

The drug should be administered to 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 the duration of intravenous treatment up to 7 days. Therefore, whenever clinically feasible, treatment should be switched from intravenous administration of Pantasan to oral pantoprazole at a dose of 40 mg.

Reflux esophagitis, 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 is 80 mg per day. If necessary, the dose may be titrated up or down depending on gastric acid secretion parameters. Doses exceeding 80 mg per day should be divided into two administrations. Temporary dose increases of pantoprazole above 160 mg may be considered, but duration of use should be limited only to the period required for adequate control of acid secretion.

If rapid reduction of acidity is needed, 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 mixing with 100 mL of 0.9% sodium chloride solution or 5% glucose solution in plastic or glass 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.

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

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

The vial is intended for single use only. Before administration, vials should be visually inspected (particularly for color change or presence of precipitate).

The diluted solution should be clear and yellowish in color.

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

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 of pantoprazole 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 have been well tolerated. Since pantoprazole is highly protein-bound, it is not a drug that is readily dialyzable.

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

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.

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), unknown (frequency cannot be determined from available data).

For all adverse reactions reported during the post-marketing period, frequency cannot be estimated; 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 for use"), hypocalcemia^1, hypokalemia^1.

Psychiatric disorders.

Uncommon: sleep disorders.

Rare: depression (including exacerbation).

Very rare: disorientation (including exacerbation).

Unknown: 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.

Unknown: 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.

Unknown: microscopic colitis.

Hepatobiliary disorders.

Uncommon: increased liver enzymes (transaminases, gamma-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^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, increased 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 for use").

^2 Muscle spasms as a result of electrolyte imbalance.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

The medicinal product is placed in a clear glass vial, closed with a grey rubber stopper sealed with aluminum and a red flip-off cap.

1 vial with the medicinal product in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

San Pharmaceutical Industries Ltd.

Manufacturer's address and place of business.

Baroda Highway, Halol, Gujarat, 389350, India