| Pharmaceutical form. Powder for solution for injection. Main physicochemical properties: white or almost white free-flowing mass and/or granular 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 H+-K+-ATPase enzyme, thus blocking the final step of gastric hydrochloric acid production. The inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. Most patients are relieved of symptoms within 2 weeks. The use of pantoprazole, as well as other proton pump inhibitors (PPIs) and H2-receptor antagonists, reduces gastric acidity and thereby increases gastrin secretion proportionally to the decrease in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds the enzyme distal to the cellular receptor, it can 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. When pantoprazole is used, fasting gastrin levels increase. With short-term use of the drug, gastrin levels in most cases do not exceed the upper limit of normal. With long-term treatment, gastrin levels increase up to two-fold in most cases. However, excessive increase occurs only in isolated cases. As a consequence, mild or moderate increase in the number of enterochromaffin-like (ECL) cells in the stomach (similar to adenomatoid hyperplasia) is sometimes observed during long-term treatment. However, according to studies conducted to date, the formation of precursor cells of neuroendocrine tumors (atypical hyperplasia) or neuroendocrine tumors of the stomach, which were observed in animal experiments, has not been observed in humans. Based on animal studies, the influence of long-term (more than one year) pantoprazole treatment on thyroid gland endocrine parameters cannot be excluded. 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 administration. Distribution. The binding of pantoprazole to plasma proteins is about 98%. The volume of distribution is about 0.15 L/kg. Biotransformation. The substance is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation by CYP2C19 with subsequent sulfate conjugation; other metabolic pathways include oxidation by CYP3A4. Elimination. The terminal half-life is about 1 hour, and clearance is 0.1 L/h/kg. Several cases of delayed elimination have been noted. Due to the specific binding of pantoprazole to proton pumps of parietal cells, the half-life does not correlate with the much longer duration of action (inhibition of acid secretion). The main part of pantoprazole metabolites is excreted in urine (about 80%), the rest is excreted in feces. The main metabolite in both serum and urine is desmethylpantoprazole conjugated with sulfate. The half-life of the main metabolite (about 1.5 hours) is slightly longer than that of pantoprazole. Special patient groups . About 3% of Europeans have functional activity of the CYP2C19 enzyme; they are called poor metabolizers. In such individuals, the metabolism of pantoprazole 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 was approximately 6 times higher in poor metabolizers than in individuals with functionally active CYP2C19 (extensive metabolizers). The mean peak plasma concentration increased by about 60%. These results do not affect pantoprazole dosing. Renal impairment . There are no dosage recommendations for dose reduction when prescribing pantoprazole to patients with renal impairment (including dialysis patients). As in healthy volunteers, the half-life of pantoprazole in patients with renal impairment is short. Only very small amounts of pantoprazole are dialyzed. Although the main metabolite has a moderately prolonged half-life (2–3 hours), elimination is still rapid, so 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 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 a 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 during studies in adults. Clinical characteristics. Indications. - Gastroesophageal reflux esophagitis.
- Duodenal ulcer.
- Gastric ulcer.
- Zollinger-Ellison syndrome and other hypersecretory pathological conditions.
Contraindications. Hypersensitivity to the active substance, benzimidazole derivatives, or any other component of the drug. Interaction with other medicinal products and other types of interactions. Medicinal products 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 proton pump inhibitors cannot be avoided, careful clinical monitoring (e.g., viral load) is recommended. The daily dose of pantoprazole should not be exceeded. Dose adjustment of HIV protease inhibitors may be necessary. Coumarin anticoagulants (phenprocoumon and warfarin). Concomitant use of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon, or INR (international normalized ratio). However, there have been reports of increased INR and prolonged prothrombin time in patients who concomitantly used PPIs and warfarin or phenprocoumon. Increased INR and prolonged prothrombin time may lead to pathological bleeding and even death. Monitoring of INR and prothrombin time is necessary when used concomitantly. Methotrexate. There have been reports that concomitant use of high-dose methotrexate (e.g., 300 mg) and proton pump inhibitors increases methotrexate blood levels in some patients. Patients receiving high doses of methotrexate, such as cancer or psoriasis patients, are advised to temporarily discontinue pantoprazole treatment. Other interactions. PANTOPRAZ 40 is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19; other metabolic pathways include, in particular, oxidation by the CYP3A4 enzyme. Studies with drugs that have the same metabolic pathways, such as carbamazepine, diazepam, glyburide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol, did not reveal clinically significant interactions. Interactions of pantoprazole with other drugs metabolized via the same enzyme system cannot be ruled out. Results of numerous studies on possible interactions indicate that pantoprazole does not affect the metabolism of active substances metabolized by CYP1A2 (e.g., caffeine, theophylline), CYP2C9 (e.g., piroxicam, diclofenac, naproxen), CYP2D6 (e.g., metoprolol), CYP2E1 (e.g., ethanol), does not affect P-glycoprotein associated with digoxin absorption. No interaction with concomitantly administered antacids has been detected. Studies on interaction of pantoprazole with concomitantly administered antibiotics (clarithromycin, metronidazole, amoxicillin) have been conducted. No clinically significant interactions between these drugs have been detected. Medicinal products that inhibit or induce CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, may increase the systemic effect of pantoprazole. Consideration should be given to dose reduction in patients receiving long-term pantoprazole therapy at high doses, and in 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. Malignant gastric tumors. Symptomatic response to pantoprazole may mask symptoms of malignant gastric tumors and delay their diagnosis. Alarm symptoms. 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, malignancy must be ruled out, since treatment with pantoprazole may mask symptoms of malignant ulcer and delay diagnosis. If symptoms persist during further adequate treatment, additional examination is required. Hepatic impairment. Patients with severe hepatic impairment should have liver enzyme levels monitored regularly, especially during long-term treatment. If liver enzyme levels increase, treatment with the drug should 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 types of interactions"). Gastrointestinal infections caused by bacteria. Treatment with pantoprazole may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or C. difficile. Sodium The drug contains less than 1 mmol of sodium (23 mg) per vial, i.e., essentially sodium-free. Hypomagnesemia. Cases of severe hypomagnesemia have been observed in patients receiving PPIs, such as pantoprazole, for at least three months, and in most cases for over a year. Serious clinical manifestations of hypomagnesemia may develop and initially go unnoticed: fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia. In cases of hypomagnesemia, patients' condition usually improved after replacement therapy with magnesium 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 determined before starting PPI therapy and periodically during treatment. Bone fractures. Long-term (more than 1 year) high-dose treatment with proton pump inhibitors may slightly increase the risk of hip, wrist, and spine fractures, primarily in elderly patients or those with other risk factors. Observational studies indicate that the use of proton pump inhibitors 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 proton pump inhibitors has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions occur, especially in areas exposed to sunlight, and are accompanied by arthralgia, the patient should consult a physician who will consider the necessity of discontinuing pantoprazole. The occurrence of subacute cutaneous lupus erythematosus in patients during previous therapy with proton pump inhibitors may increase the risk of its development when using other proton pump inhibitors. Use during pregnancy or breastfeeding. Pregnancy. Available data on the use of pantoprazole in pregnant women (approximately 300–1000 reports on pregnancy outcomes) indicate the absence of embryonal or fetal/neonatal toxicity of the drug. Reproductive toxicity was observed in animal studies. As a precaution, pantoprazole should be avoided in pregnant women. Breastfeeding. Animal studies have shown excretion of pantoprazole in breast milk. There is insufficient data 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 to discontinue/abstain from pantoprazole treatment should be made considering 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 influence reaction speed when driving or operating machinery. PANTOPRAZ 40 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 taken into account (see section "Adverse reactions"). In such cases, driving or operating machinery should be avoided. Administration and dosage. The drug is administered to adults as prescribed and under direct medical supervision. Intravenous administration of the drug is recommended only if oral administration is not possible. Data on the duration of intravenous treatment are up to 7 days. Therefore, when clinically feasible, transition from intravenous to oral pantoprazole administration should be performed. Treatment of gastroesophageal reflux esophagitis, duodenal ulcer, gastric ulcer. The recommended dose is 40 mg of PANTOPRAZ 40 (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 PANTOPRAZ 40 is 80 mg daily. If necessary, the dose can be titrated up or down depending on gastric acid secretion parameters. Doses exceeding 80 mg daily should be divided into two administrations. Temporary increase of pantoprazole dose to more than 160 mg is possible, but the 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 80 x 2 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 with the powder. The solution can 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 point of view, the diluted drug should be used immediately. PANTOPRAZ 40 should 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 remaining drug or drug with altered physicochemical properties (e.g., color change, precipitate formation) must be disposed of according to local regulations. The diluted solution should have a clear yellowish color. Patients with hepatic impairment. Patients with severe hepatic impairment should not exceed a daily dose of 20 mg (½ vial of PANTOPRAZ 40, powder for solution for injection, 40 mg). Patients with renal impairment. Patients with renal impairment do not require dose adjustment. Elderly patients do not require dose adjustment. Children. PANTOPRAZ 40, 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. 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 is not a drug that can be easily removed by dialysis. In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy should be administered. There are no recommendations for specific therapy. Adverse reactions. Adverse reactions were observed in about 5% of patients. The most common adverse reactions were diarrhea and headache (about 1%). Adverse effects by frequency of occurrence are classified 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), unknown (frequency cannot be determined from available data). Blood and lymphatic system. Rare: agranulocytosis. Very rare: leukopenia, thrombocytopenia, pancytopenia. Immune system. 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"), hypocalcemia1, hypokalemia. Psychiatric disorders. Uncommon: sleep disorders. Rare: depression (including exacerbation). Very rare: disorientation (including exacerbation). Unknown: hallucinations, confusion (especially in patients predisposed to these disorders, and including exacerbation of these symptoms if previously present). Nervous system. Uncommon: headache, dizziness. Rare: taste disturbances. Unknown: paresthesia. Eye disorders. Rare: visual disturbances/blurred vision. Gastrointestinal disorders. Uncommon: diarrhea, nausea, vomiting, abdominal distension, constipation, dry mouth, abdominal pain and discomfort. Hepatobiliary system. Uncommon: increased liver enzymes (transaminases, γ-GT). Rare: increased bilirubin levels. Unknown: hepatocyte injury, jaundice, hepatocellular insufficiency. Skin and subcutaneous tissue. Uncommon: skin rashes, exanthema, pruritus. Rare: urticaria, angioedema. Unknown: Stevens-Johnson syndrome, Lyell's syndrome, erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special precautions for use"). Musculoskeletal and connective tissue. Uncommon: hip, wrist, spine fractures (see section "Special precautions for use"). Rare: arthralgia, myalgia. Unknown: muscle spasms2. Renal and urinary system. Unknown: interstitial nephritis (with possible development of renal failure). Reproductive system and breast. Rare: gynecomastia. General disorders. Uncommon: asthenia, fatigue, malaise. Rare: increased body temperature, peripheral edema. 1 Hypocalcemia simultaneously with hypomagnesemia. 2 Muscle spasms as a result of electrolyte imbalance. Shelf life. 3 years. From a microbiological point of view, the diluted drug should be used immediately. However, the physicochemical stability of the diluted drug is maintained for 12 hours at 25 °C. Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging. Keep out of reach of children. Packaging. Powder for solution for injection in vial. 1 vial per cardboard box. Prescription status. Prescription only. Manufacturer. Reyoung Pharmaceutical Co., Ltd. Reyoung Pharmaceutical Co., Ltd. Manufacturer's address and place of business. No.1, Ruiyang Road, Yiyuan County, Shandong Province, People's Republic of China No.1 Ruiyang Road, Yiyuan County, Shandong Province, P.R.China Marketing authorization holder. GREEN BUSINESS SOLUTIONS SA / GREEN BUSINESS SOLUTIONS SA Marketing authorization holder's address: Rue Mercerie 12, c/o Drys Fiduciaire SA, 1003 Lausanne, Switzerland Rue Mercerie 12, c/o Drys Fiduciaire SA, 1003 Lausanne, Switzerland |
