| Pharmaceutical form. Powder for solution for injection. Main physicochemical properties: white or almost white lyophilized powder. Diluted solution – clear solution ranging from colorless to yellowish. Pharmacotherapeutic group. Drugs for treatment of acid-related diseases. 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 the proton pumps of parietal cells. Pantoprazole is transformed into its active form in the acidic environment of parietal cells, where it inhibits the H+-K+-ATPase enzyme, thus blocking the final step of gastric hydrochloric acid production. Inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, symptoms disappear within 2 weeks. The use of pantoprazole, as well as other proton pump inhibitors (PPIs) and H2-receptor inhibitors, reduces gastric acidity and thereby increases gastrin secretion proportionally to the decrease in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds to the enzyme outside the cellular receptor, it may inhibit hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect of oral and intravenous administration of the drug is the same. Administration of pantoprazole increases fasting gastrin levels. With short-term use, it usually does not exceed the upper limit of normal. With long-term treatment, gastrin levels increase twofold in most cases. Excessive elevation occurs only in isolated cases. As a consequence, mild or moderate increase of specific enterochromaffin-like (ECL) cells in the stomach (similar to adenomatoid hyperplasia) may occasionally be observed during prolonged treatment. However, according to currently conducted studies, the formation 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, 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. In addition, due to decreased gastric acidity, chromogranin A (CgA) levels rise. Elevated CgA levels may affect test results when diagnosing 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 normal ranges. Pharmacokinetics. Pharmacokinetic properties do not change after single or repeated administration of the drug. In the dose range of 10 to 80 mg, the pharmacokinetics of pantoprazole in blood plasma remain linear both after oral administration and intravenous injection. Distribution. Pantoprazole binding to plasma proteins is approximately 98%, volume of distribution is approximately 0.15 L/kg. Biotransformation. The substance is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation via CYP2C19 with subsequent sulfate conjugation; other metabolic pathways include oxidation via CYP3A4. Elimination. Terminal half-life is approximately 1 hour, clearance is 0.1 L/h/kg. Several cases of delayed elimination have been recorded. Due to the specific binding of pantoprazole to proton pumps of parietal cells, the elimination half-life does not correlate with the much longer duration of action (inhibition of acid secretion). The majority of pantoprazole metabolites are excreted in urine (approximately 80%), the remainder is excreted in feces. The main metabolite in both serum and urine is desmethylpantoprazole conjugated with sulfate. The half-life of the main metabolite (approximately 1.5 hours) slightly exceeds that of pantoprazole. Special patient groups Slow metabolizers. Approximately 3% of Europeans have low functional activity of the CYP2C19 enzyme; they are called slow metabolizers. In these individuals, pantoprazole metabolism is likely catalyzed mainly 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 slow metabolizers than in individuals with functionally active CYP2C19 (fast metabolizers). The mean peak plasma concentration increased by approximately 60%. These results do not affect pantoprazole dosing. Renal impairment. No dosage recommendations are required when prescribing pantoprazole to patients with impaired renal function (including dialysis patients). As in healthy volunteers, the elimination half-life of pantoprazole in these patients is short. Only a very small amount of pantoprazole is dialyzed. Despite the moderately prolonged half-life of the main metabolite (2–3 hours), elimination is still rapid, so accumulation does not occur. Hepatic impairment. Although in patients with liver cirrhosis (Child classes A and B) the elimination 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 is also 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 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 pathological conditions.
Contraindications. Hypersensitivity to the active substance, benzimidazole derivatives, or any component of the drug. Interaction with other medicinal products and other forms of interaction. Drugs whose absorption depends on pH. Due to complete and prolonged inhibition of hydrochloric acid secretion, pantoprazole may affect the absorption of drugs for which gastric juice pH is an important factor for their bioavailability (e.g., certain antifungal agents such as ketoconazole, itraconazole, posaconazole, or other drugs such as erlotinib). HIV protease inhibitors. Concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir), whose absorption depends on intragastric pH, is not recommended due to 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 concomitant PPIs with warfarin or phenprocoumon. Increased INR and prolonged prothrombin time may lead to pathological bleeding and even fatal outcomes. Monitoring of INR and prothrombin time is necessary in such concomitant use. Methotrexate. It has been reported that concomitant use of high-dose methotrexate (e.g., 300 mg) and PPIs increases methotrexate blood levels in some patients. Patients receiving high-dose methotrexate, e.g., for cancer or psoriasis, are advised to temporarily discontinue pantoprazole treatment. Other interactions. Pantoprazole is mainly metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation via CYP2C19; other metabolic pathways include oxidation by CYP3A4. Studies with drugs 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 of several studies on possible interactions indicate that pantoprazole does not affect the metabolism of active substances metabolized via CYP1A2 (e.g., caffeine, theophylline), CYP2C9 (e.g., piroxicam, diclofenac, naproxen), CYP2D6 (e.g., metoprolol), CYP2E1 (e.g., ethanol), and does not affect P-glycoprotein associated with digoxin absorption. No interaction was found with concomitantly administered antacids. Studies on interaction between pantoprazole and concomitantly administered certain antibiotics (clarithromycin, metronidazole, amoxicillin) were also conducted. No clinically significant interactions between these drugs were found. Drugs that inhibit or induce CYP2C19. CYP2C19 inhibitors such as fluvoxamine may increase systemic exposure to pantoprazole. Consideration should be given to dose reduction for patients receiving long-term high-dose pantoprazole therapy and for patients with hepatic impairment. 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. Special precautions for use. Gastric malignancies. Symptomatic response to pantoprazole may mask symptoms of gastric malignancies and delay their diagnosis. In the presence of alarm symptoms (e.g., significant weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena), as well as suspicion or presence of gastric ulcer, the presence of a malignant process must be excluded. If symptoms persist despite adequate treatment, additional examination is required. Hepatic impairment. Patients with severe hepatic impairment require regular monitoring of liver enzymes. If liver enzyme levels increase, treatment with the drug must be discontinued (see section "Dosage and administration"). HIV protease inhibitors. Concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir), whose absorption depends on intragastric pH, is not recommended due to significant reduction in their bioavailability (see section "Interaction with other medicinal products and other forms of interaction"). Gastrointestinal infections caused by bacteria. Treatment with Pelta® may slightly increase 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 (23 mg) of sodium per vial, i.e., practically sodium-free. Hypomagnesemia. Cases of severe hypomagnesemia have rarely been observed in patients treated with PPIs such as pantoprazole for at least three months, and in most cases for one year. Serious clinical manifestations of hypomagnesemia such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia may develop insidiously and remain undetected. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia (see section "Adverse reactions"). In cases of hypomagnesemia (and hypocalcemia associated with hypomagnesemia), patients' conditions mostly improved after replacement corrective therapy with magnesium supplements and discontinuation of PPIs. Patients requiring long-term therapy, or patients taking PPIs concomitantly with digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), should have magnesium levels measured before starting PPI therapy and periodically during treatment. Bone fractures. Long-term treatment (more than 1 year) with high doses of PPIs may moderately increase the risk of hip, wrist, and spine fractures, primarily 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 may be due to other risk factors. Patients at risk of developing osteoporosis should receive treatment according to current clinical guidelines and consume adequate amounts of vitamin D and calcium. Subacute cutaneous lupus erythematosus. The use of PPIs has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions occur, especially in areas exposed to sunlight, accompanied by arthralgia, the patient should immediately consult a physician who will consider the necessity of discontinuing Pelta®. Previous PPI therapy leading to subacute cutaneous lupus erythematosus may increase the risk of its development when using other PPIs. Effect on laboratory test results Elevated CgA levels may affect test results when diagnosing neuroendocrine tumors. To avoid such influence, Pelta® 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 ranges after initial measurement, repeat measurements should be performed 14 days after discontinuation of PPI treatment. Use during pregnancy or breastfeeding. Pregnancy. Available data on pantoprazole use in pregnant women (approximately 300–1000 pregnancy outcomes reported) indicate no embryonic or fetoneonatal toxicity of the drug. Reproductive toxicity was observed in animal studies. As a precaution, use of Pelta® in pregnant women should be avoided. Lactation period. Animal studies showed excretion of pantoprazole in breast milk. Insufficient data are available on excretion of pantoprazole in human breast milk, but such excretion has been reported. Risk to newborns/infants cannot be excluded. The decision to discontinue breastfeeding or discontinue/abstain from Pelta® treatment should be made considering the benefits of breastfeeding for the child and the benefits of Pelta® treatment for the woman. Fertility. Pantoprazole did not impair fertility in animal studies. Ability to affect reaction speed when driving or operating machinery. Pantoprazole does not affect or has a very slight effect on reaction speed when driving or operating machinery. Possible development of adverse reactions such as dizziness and visual disturbances should be considered (see section "Adverse reactions"). In such cases, driving or operating machinery should be avoided. Administration and dosage. The drug should be used only as prescribed by a physician and under appropriate medical supervision. Intravenous administration of the drug is recommended only if oral administration is not possible. Data are available on intravenous treatment duration up to 7 days. Therefore, as soon as oral administration of pantoprazole becomes possible, transition from intravenous administration of Pelta® to oral administration of pantoprazole at a dose of 40 mg should be made. Gastroesophageal reflux disease, duodenal ulcer, gastric ulcer The recommended dose is 40 mg of pantoprazole (1 vial) daily intravenously. Treatment of Zollinger-Ellison syndrome and other hypersecretory pathological conditions For long-term treatment of Zollinger-Ellison syndrome and other hypersecretory pathological conditions, the recommended initial dose of Pelta® 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 increase in pantoprazole dose to more than 160 mg is possible, but duration of use should be limited only to the period necessary 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 Dissolve the powder in 10 mL of 0.9% sodium chloride solution added to the vial. The resulting 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 vials. After dilution, the chemical and physical stability of the drug is maintained for 12 hours at 25 °C. From a microbiological safety standpoint, the diluted preparation should be used immediately. The medicinal product Pelta® 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. Any unused drug or drug with changed physicochemical properties (e.g., color change, precipitate formation) must be disposed of according to local legislation. The diluted solution should be clear, colorless to yellowish. Hepatic insufficiency. Patients with severe hepatic impairment should not exceed a daily dose of 20 mg (½ vial of Pelta®, powder for solution for injection 40 mg) (see section "Special precautions for use"). Renal insufficiency. Patients with impaired renal function do not require dose adjustment. Elderly patients do not require dose adjustment. Children. Pelta®, powder for solution for injection, 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 data are described in the "Pharmacokinetics" section, but dosage recommendations cannot be provided. Overdose. Symptoms of overdose are unknown. Doses up to 240 mg administered intravenously over 2 minutes were well tolerated. Since pantoprazole is extensively protein-bound, it does not belong to drugs easily removed by dialysis. In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy should be applied. No recommendations for specific therapy are available. Adverse reactions. Adverse reactions can 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 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10000 and <1/1000), very rare (<1/10000), frequency not known (frequency cannot be determined 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"), hypocalcemia1, hypokalemia1. Psychiatric disorders Uncommon: sleep disorders. Rare: depression (including exacerbation). Very rare: disorientation (including exacerbation). Frequency not known: hallucinations, confusion (especially in patients predisposed to such disorders, including exacerbation of these symptoms if previously present). Nervous system disorders Uncommon: headache, dizziness. Rare: taste disturbances. Frequency not known: 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. Frequency not known: microscopic colitis. Hepatobiliary disorders Uncommon: increased liver enzymes (transaminases, γ-GT). Rare: increased bilirubin levels. Frequency not known: hepatocyte injury, jaundice, hepatocellular insufficiency. Skin and subcutaneous tissue disorders Uncommon: skin rashes, exanthema, pruritus. Rare: urticaria, angioneurotic edema. Frequency not known: Stevens-Johnson syndrome, Lyell's syndrome, erythema multiforme, photosensitivity, drug reaction with eosinophilia and systemic symptoms (DRESS), subacute cutaneous lupus erythematosus (see section "Special precautions for use"). Musculoskeletal and connective tissue disorders Uncommon: hip, wrist, spine fractures (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 injection site. Uncommon: asthenia, fatigue, malaise. Rare: increased body temperature, peripheral edema. 1 Hypocalcemia and/or hypokalemia may be associated with hypomagnesemia (see section "Special precautions for use"). 2 Muscle spasms as a result of electrolyte imbalance. Shelf life. 2 years from the date of manufacture in bulk. After reconstitution, the medicinal product is suitable for use for 12 hours when stored at 25 ± 2 °C in an inverted vial. Do not use the medicinal product after the expiry date stated on the packaging. Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children. Packaging. 1 vial per pack. Prescription status. Prescription only. Manufacturer. JSC "Farmak", Ukraine (secondary packaging, batch release from bulk product of the manufacturer Demo S.A. Pharmaceutical Industry, Greece). Manufacturer's address and place of business. Ukraine, 04080, Kyiv, Kyrylivska St., 74. |
