INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PANTOPRAZOLE (PARASTAMIK)

Composition:

Active substance: pantoprazole;

1 vial contains 45.12 mg of sodium pantoprazole (as sesquihydrate), equivalent to 40 mg of pantoprazole;

Excipients: mannitol (E 421), sodium citrate, sodium hydroxide.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or almost white powder.

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

Pharmacological properties.

Pharmacodynamics.

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 enzyme H⁺-K⁺-ATPase, thereby blocking the final step of gastric hydrochloric acid production. Inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. In most patients, symptoms resolve within 2 weeks. As with other proton pump inhibitors (PPIs) and H₂-receptor antagonists, pantoprazole reduces gastric acidity and consequently increases gastrin secretion proportionally to the reduction in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds to the enzyme distal to the cellular receptor, it can inhibit hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same following oral and intravenous administration.

Pharmacodynamic effects. Pantoprazole increases fasting gastrin levels. With short-term use, gastrin levels in most cases do not exceed the upper limit of normal. With long-term treatment, gastrin levels typically increase twofold, although marked elevation occurs only occasionally. As a consequence, during prolonged therapy, a slight or moderate increase in the number of enterochromaffin-like (ECL) cells in the stomach (similar to adenomatoid hyperplasia) may be observed in a small number of cases. However, according to studies conducted to date, development of precursor cells of neuroendocrine tumors (atypical hyperplasia) or gastric neuroendocrine tumors, as observed in animal experiments, has not been reported in humans.

Based on animal studies, a potential effect 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 increase. Elevated CgA levels may interfere with diagnostic tests 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 to return to the normal range, which may otherwise be falsely elevated after PPI treatment.

Pharmacokinetics.

General pharmacokinetics. Pharmacokinetic properties do not change after single or repeated administration. In the dose range of 10 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 almost exclusively metabolized in the liver. The main metabolic pathway is demethylation via CYP2C19, followed by sulfate conjugation; 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 observed. 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 effect (acid secretion inhibition).

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

Special patient groups

Poor metabolizers. Approximately 3% of Europeans have low functional activity of the CYP2C19 enzyme and are referred to as poor metabolizers. In these individuals, pantoprazole metabolism is likely 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 for pantoprazole in patients with renal impairment, including those on dialysis. As in healthy individuals, 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 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 (C_max) 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 relationship was observed between pantoprazole clearance and patient age or body weight. AUC and volume of distribution were consistent with data obtained from adult studies.

Clinical characteristics.

Indications.

Gastroesophageal reflux disease (GERD).
Duodenal ulcer.
Gastric ulcer.
Zollinger–Ellison syndrome and other hypersecretory pathological conditions.

Contraindications.

Hypersensitivity to pantoprazole, benzimidazole derivatives, or to any other component of the drug.

Interaction with other medicinal products and other forms of interaction.

Effect of pantoprazole on the absorption of other medicinal products.
Due to complete and prolonged inhibition of gastric acid secretion, pantoprazole may reduce the absorption of drugs whose bioavailability depends on gastric pH (e.g., certain azole antifungal agents such as ketoconazole, itraconazole, posaconazole, or other drugs such as erlotinib).

Antiretroviral drugs (atazanavir).
Concomitant use of proton pump inhibitors (PPIs) with atazanavir and other antiretroviral drugs whose absorption is pH-dependent may lead to a significant reduction in their bioavailability and affect their efficacy. Therefore, concomitant use of PPIs with atazanavir is not recommended (see section "Special precautions for use").

In cases where concomitant use of HIV protease inhibitors with PPIs cannot be avoided, careful clinical monitoring (e.g., monitoring of 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. When these drugs are used concomitantly, monitoring of INR and prothrombin time is required.

Methotrexate.
There have been reports of increased blood levels of methotrexate in some patients when high-dose methotrexate (e.g., 300 mg) is administered concomitantly with PPIs. Patients receiving high doses of methotrexate, such as those with cancer or psoriasis, should temporarily discontinue pantoprazole therapy.

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

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

Results from multiple 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), or CYP2E1 (e.g., ethanol). It does not affect P-glycoprotein associated with digoxin absorption.

No interactions have been observed with concomitantly administered antacids.

Studies investigating the interaction of pantoprazole with certain concomitantly administered antibiotics (clarithromycin, metronidazole, amoxicillin) have not revealed clinically significant interactions.

Medicinal products that inhibit or induce CYP2C19.
Inhibitors of CYP2C19, such as fluvoxamine, may increase the systemic exposure to pantoprazole. A dose reduction should be considered 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.

Effect of the drug on laboratory test results

False-positive results in certain urine screening tests for tetrahydrocannabinol (THC) have been reported in patients taking pantoprazole. Alternative testing methods should be considered to confirm test results.

Special precautions for use.

Malignant gastric tumors. 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 case 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 liver dysfunction should have regular monitoring of liver enzymes, especially during prolonged treatment. If liver enzymes increase, treatment with the medicinal product should be discontinued (see section "Dosage and administration").

Combination therapy. When using combination therapy, instructions in the respective product information leaflets should be followed.

Concomitant use with atazanavir. Concomitant use of PPIs with atazanavir is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If combination of pantoprazole with atazanavir is necessary, careful clinical monitoring (e.g., measurement of viral load) should be performed, along with increasing the atazanavir dose to 400 mg in combination with 100 mg ritonavir. The pantoprazole dose should not exceed 20 mg daily.

Effect on vitamin B12 absorption. In patients with Zollinger–Ellison syndrome and other pathological hypersecretory conditions requiring long-term treatment, pantoprazole, like all acid-blocking medicinal products, may reduce vitamin B12 (cyanocobalamin) absorption due to hypo- or achlorhydria. This should be considered in patients with low body stores of vitamin B12 or with risk factors for reduced vitamin B12 absorption during long-term therapy or in the presence of relevant clinical symptoms.

Long-term therapy. During long-term therapy, especially when exceeding treatment duration of 1 year, patients should be regularly monitored.

Gastrointestinal infections caused by bacteria. Pantoprazole, like other PPIs, 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, Campylobacter, or C. difficile.

Sodium. The medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e., 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 after 1 year. Serious clinical manifestations of hypomagnesaemia such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias may occur and may initially develop insidiously. In cases of hypomagnesaemia, 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 other drugs that may cause hypomagnesaemia (e.g., diuretics), should have serum magnesium levels measured before starting PPI treatment and periodically during treatment.

Bone fractures. PPIs, particularly when used at high doses and over a prolonged period (more than 1 year), may slightly increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or in the presence of other existing risk factors. Observational studies suggest that PPI use 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 (SCAR)

Severe cutaneous adverse reactions have been reported with pantoprazole use, including erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be life-threatening or fatal. The frequency of these reactions is unknown (see section "Adverse reactions").

When prescribing pantoprazole, patients should be informed about the signs and symptoms and closely monitored for skin reactions. If signs or symptoms suggestive of these severe skin reactions occur, pantoprazole should be discontinued immediately and alternative treatment options considered.

Subacute cutaneous lupus erythematosus (SCLE). 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, the patient should seek immediate medical advice, and discontinuation of pantoprazole should be considered. Development of SCLE in patients during previous PPI therapy may increase the risk of recurrence when other PPIs are used.

Effect on laboratory test results

Elevated levels of chromogranin A (CgA) may interfere with diagnostic tests for neuroendocrine tumors. To avoid this interference, treatment with Parastamik 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 PPI treatment.

Use during pregnancy or breastfeeding.

Pregnancy. Experience with the use of pantoprazole in pregnant women is limited. Reproductive toxicity was observed in animal studies. The potential risk to humans is unknown. Parastamik should not be used during pregnancy except in cases of clear medical need.

Breastfeeding. Animal studies have shown excretion of pantoprazole into breast milk. Data are available on excretion of pantoprazole into human breast milk. A decision on whether to discontinue breastfeeding or to discontinue/abstain from Parastamik treatment should be made taking into account the benefit of breastfeeding for the child and the benefit of treatment 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. However, 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 or operating machinery should be avoided.

Dosage and Administration

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, the transition should be made from intravenous 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) once daily 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 Parastamik 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. Temporary dose increases of pantoprazole to more than 160 mg may be considered, but the duration of such treatment should be limited to the period required for adequate control of acid secretion.

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

Preparation for use

The powder should be dissolved in 10 mL of 0.9% sodium chloride solution provided in the vial. The resulting 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 medication is maintained for 12 hours at 25°C. From a microbiological standpoint, the diluted solution should be used immediately.

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

The intravenous infusion should be administered over 2–15 minutes.

The vial is intended for single use only. Any unused portion or medication with altered physicochemical properties (e.g., color change, precipitation) must be discarded according to local regulations.

The reconstituted solution must be clear and colorless.

Hepatic impairment

Patients with severe hepatic impairment should not exceed a daily dose of 20 mg (½ vial of Parastamik, 40 mg powder) (see section "Special precautions").

Renal impairment

Patients with impaired renal function do not require dose adjustment.

Elderly patients do not require dose adjustment.

Children

Experience with the use of this medicinal product in children is limited. Therefore, the drug is not recommended for use in children (under 18 years of age) until additional data become available.

Overdose

Symptoms of overdose are unknown.

Doses up to 240 mg administered intravenously over 2 minutes have been well tolerated. Since pantoprazole is highly protein-bound, it is not readily dialyzable.

In the event 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 into the following categories: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (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: 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), change in body weight.

Frequency not known: hyponatremia, hypomagnesemia (see section "Special precautions for use"), hypocalcemia¹, hypokalemia.

Psychiatric disorders

Uncommon: sleep disorders.

Rare: depression (including exacerbation).

Very rare: confusion (including exacerbation).

Frequency not known: hallucinations, disorientation (particularly in patients predisposed to such disorders, and including exacerbation of these symptoms if pre-existing).

Nervous system disorders

Uncommon: headache, dizziness.

Rare: taste disorders.

Frequency not known: paraesthesia.

Eye disorders

Rare: visual disturbances/blurred vision.

Gastrointestinal disorders

Common: fundic gland polyps (benign).

Uncommon: diarrhea, nausea, vomiting, abdominal distension, 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, toxic epidermal necrolysis (Lyell's syndrome), 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.

Frequency not known: muscle spasms².

Renal and urinary disorders

Frequency not known: interstitial 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 concurrent with hypomagnesemia.

² Muscle spasms as a consequence of electrolyte imbalance.

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years. The shelf life of the prepared solution is 12 hours.

Storage conditions. Store in the original packaging, in a place protected from light and inaccessible to children, at a temperature not exceeding 25°C.

Incompatibilities. The medicinal product must not be mixed with any other medicinal products except those specified in the section "Instructions for use and dosage".

Packaging. 1, 5, or 10 vials per cardboard box.

Prescription status. Prescription only.

Manufacturers.

DEMO SA Pharmaceutical Industry.

Manufacturer's address and location of operations.

21st km National Road Athens – Lamia, Krioneri Attikis, 145 68, Greece /
21st km National Road Athens - Lamia, Krioneri Attikі, 14568, Greece.

Parastamic