Pantoprazole-pharmex
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PANTOPRAZOLE-PHARMEX (PANTOPRAZOLE-PHARMEX)
Composition:
active substance: pantoprazole;
1 vial contains sodium pantoprazole sesquihydrate equivalent to pantoprazole 40.0 mg;
excipients: disodium edetate, sodium hydroxide.
Pharmaceutical form. Lyophilisate for solution for injection.
Main physico-chemical properties: lyophilized porous mass or powder, white to almost white.
Pharmacotherapeutic group.
Drugs for treatment of acid-related disorders. Proton pump inhibitors.
ATC code A02B C02.
Pharmacological Properties
Pharmacodynamics
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 enzyme H+-K+-ATPase, thereby blocking the final step of hydrochloric acid production in the stomach. The inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. These effects disappear in most patients within 2 weeks. The use of pantoprazole, as well as other proton pump inhibitors (PPIs) and H2-receptor inhibitors, 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 hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is equivalent following both oral and intravenous administration.
Administration of 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. Excessive elevation of gastrin, however, is rare. As a consequence, prolonged therapy may occasionally lead to mild or moderate increase in the number of enterochromaffin-like cells (ECL cells) in the stomach (similar to adenomatoid hyperplasia). However, according to studies conducted to date, the formation of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors has not been observed in humans.
Based on animal studies, 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 treatment with proton pump inhibitors should be discontinued for a period of 5 days to 2 weeks prior to measuring CgA levels. This allows CgA levels, which may be falsely elevated after PPI treatment, to return to the normal range.
Pharmacokinetics
Absorption. Pantoprazole is rapidly absorbed, and maximum plasma concentration (Cmax) is achieved after a single oral dose of 40 mg. On average, peak serum concentration of approximately 2–3 µg/mL is reached within 2.5 hours after administration; plasma concentrations remain stable with repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. Within the dose range of 10 to 80 mg, the pharmacokinetics of pantoprazole in plasma remain linear, both after oral administration and intravenous infusion. Absolute bioavailability of the tablets is approximately 77%. Concomitant food intake does not affect the area under the concentration-time curve (AUC) or Cmax, and therefore does not affect bioavailability. Food intake only increases the variability of the lag time.
Distribution. Protein binding of pantoprazole to serum proteins is approximately 98%. The volume of distribution is about 0.15 L/kg.
Biological transformation. Pantoprazole is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation by CYP2C19, followed by sulfate conjugation; another metabolic pathway involves oxidation by 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 (about 80%), with the remainder eliminated in feces. The main metabolite in both serum 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 populations
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 of pantoprazole, 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 recommendations.
Renal impairment. No dosage adjustment is recommended for pantoprazole in patients with impaired renal function, including those on dialysis. As in healthy volunteers, the elimination half-life of pantoprazole remains short. Only a very small amount of pantoprazole is dialyzable. Despite the moderately prolonged half-life of the main metabolite (2–3 hours), elimination remains rapid, and therefore accumulation does not occur.
Hepatic impairment. Although in patients with liver cirrhosis (Child-Pugh classes A and B) the elimination 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. The slight increase in AUC and Cmax observed in elderly volunteers compared to younger volunteers is not clinically significant.
Pediatric patients. After a single oral dose of 20 or 40 mg pantoprazole, AUC and Cmax values in children aged 5 to 16 years were within the range observed in adults. After a single intravenous dose of 0.8 or 1.6 mg/kg pantoprazole administered 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 in adult studies.
Clinical characteristics.
Indications.
Gastroesophageal reflux disease (reflux esophagitis).
Duodenal ulcer.
Gastric ulcer.
Zollinger-Ellison syndrome and other hypersecretory conditions.
Contraindications.
Hypersensitivity to pantoprazole, benzimidazole derivatives, or to any of the other components of the medicinal product.
Interaction with other medicinal products and other forms of interaction.
Effect of pantoprazole on absorption of other medicinal products. Due to complete and prolonged inhibition of hydrochloric acid secretion, pantopraise may reduce the absorption of medicinal products whose bioavailability is pH-dependent (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 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 PPIs concomitantly 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 required when these drugs are used concomitantly.
Methotrexate. There have been reports that concomitant use of high-dose methotrexate (e.g., 300 mg) and proton pump inhibitors increases blood levels of methotrexate in some patients. Patients receiving high-dose methotrexate, such as those with cancer or psoriasis, should temporarily discontinue pantoprazole therapy.
Medicinal products that inhibit or induce CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, may increase systemic exposure to pantoprazole. Consideration should be given to dose reduction in patients undergoing long-term high-dose pantoprazole therapy 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.
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 metabolism via CYP3A4. Studies with medicinal products also metabolized through these pathways—such as carbamazepine, diazepam, glyburide (glibenclamide), nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—have not revealed clinically significant interactions.
Interaction between pantoprazole and other drugs metabolized via the same enzyme systems cannot be ruled out.
It has been established that pantoprazole does not affect the metabolism of active substances metabolized by CYP1A2 (such as caffeine, theophylline), CYP2C9 (such as piroxicam, diclofenac, naproxen), CYP2D6 (such as metoprolol), or CYP2E1 (such as ethanol). Pantoprazole does not affect P-glycoprotein, which mediates digoxin absorption.
No interaction has been observed with concomitantly administered antacids.
No clinically significant interactions have been reported between pantoprazole and concomitantly administered antibiotics (clarithromycin, metronidazole, amoxicillin).
Special precautions for use.
Malignant gastric neoplasms. 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 excluded, since treatment with pantoprazole may mask symptoms of malignant ulcer and delay diagnosis. If symptoms persist during continued adequate therapy, further investigations are required.
Hepatic impairment. Patients with severe hepatic impairment require regular monitoring of liver enzymes. If liver enzyme levels increase, treatment with the drug should be discontinued.
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 significantly reduced bioavailability (see section "Interaction with other medicinal products and other forms of interaction").
Vitamin B12 absorption. In patients with Zollinger–Ellison syndrome and other hypersecretory conditions requiring long-term treatment, pantoprazole, like all agents that inhibit gastric acid production, may reduce absorption of vitamin B12 (cyanocobalamin) due to the development of hypo- or achlorhydria. This should be considered in patients with weight loss, risk factors for reduced vitamin B12 absorption during prolonged therapy, or presence of relevant clinical symptoms.
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. This medicinal product contains less than 1 mmol (23 mg)/dose (vial) of sodium, i.e., essentially "sodium-free".
Hypomagnesemia. Cases of severe hypomagnesemia have been reported in patients treated with proton pump inhibitors (PPIs), such as pantoprazole, for at least 3 months, and in most cases, for over a year. Severe manifestations of hypomagnesemia, such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia, may develop insidiously and may be overlooked. In most cases, the condition improved after magnesium replacement therapy and discontinuation of PPI treatment.
Patients who are planned for long-term therapy or who are taking PPIs concomitantly with digoxin or medications that may cause hypomagnesemia (e.g., diuretics) should have their magnesium levels measured before starting PPI therapy and periodically during treatment.
Bone fractures. Proton pump inhibitors, particularly when used at high doses and over a long duration (more than 1 year), may slightly increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other existing risk factors. Studies have shown that PPIs may increase the overall fracture risk by 10–40%. Some of these fractures may be attributable to other risk factors. Patients at risk of developing osteoporosis should receive treatment according to current clinical guidelines and adequate intake of vitamin D and calcium.
Severe cutaneous adverse reactions. Severe cutaneous adverse reactions associated with the use of pantoprazole, which may be life-threatening or lead to fatal outcomes, have been reported, including erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). The frequency of these reactions is unknown (see section "Adverse reactions"). Patients should be informed about the signs and symptoms and closely monitored. If symptoms suggestive of these reactions occur, pantoprazole should be discontinued immediately and alternative treatment 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 the drug should be considered. Development of subacute cutaneous lupus erythematosus in patients during prior therapy with proton pump inhibitors may increase the risk of recurrence when using other proton pump inhibitors.
Effect on laboratory test results.
Elevated chromogranin A (CgA) levels may interfere with diagnostic tests for neuroendocrine tumors. To avoid such interference, treatment with the drug should be temporarily discontinued at least 5 days before assessment of 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 proton pump inhibitor therapy.
Use during pregnancy or breastfeeding.
Pregnancy. Available data on the use of pantoprazole in pregnant women indicate no embryonal or fetal/neonatal toxicity of the drug. Reproductive toxicity was observed in animal studies. As a precautionary measure, use of the drug in pregnant women should be avoided.
Breastfeeding. Animal studies have shown excretion of pantoprazole into breast milk. There is insufficient data on excretion of pantoprazole into 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 treatment with the drug should be made taking into account the benefit of breastfeeding for the child and the benefit of treatment with the drug 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 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 considered. In such cases, driving or operating machinery should be avoided.
Method of Administration and Dosage
The drug should be used by adults only as prescribed and under direct medical supervision.
Intravenous administration of the drug is recommended only when oral pantoprazole cannot be administered. Data are available on intravenous treatment duration up to 7 days. Therefore, when clinically feasible, transition from intravenous to oral pantoprazole should be performed.
Gastroesophageal reflux disease, 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 of pantoprazole is 80 mg per day. If necessary, the dose may be titrated upward or downward depending on gastric acid secretion parameters. Doses exceeding 80 mg per day should be divided into two administrations. A temporary increase in pantoprazole dose up 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.
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 infusion 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.
Pantoprazole 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 reconstituted solution should be clear and yellowish in color.
Hepatic impairment. In patients with severe hepatic impairment, the daily dose should not exceed 20 mg (½ vial of pantoprazole, 40 mg powder).
Renal impairment. Dose adjustment is not required in patients with impaired renal function.
Elderly patients do not require dose adjustment.
Children.
Pantoprazole is not recommended for use in children (under 18 years of age), as data on safety and efficacy 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 were well tolerated. Since pantoprazole is extensively protein-bound, it is not 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 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 about 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 (≥ 1/10000 and < 1/1000), very rare (< 1/10000), 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 "not known".
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
Not known: hyponatremia, hypomagnesemia, hypocalcemia1, hypokalemia
Psychiatric disorders
Uncommon: sleep disorders
Rare: depression (including exacerbation)
Very rare: disorientation (including exacerbation)
Not known: hallucinations, confusion (particularly in patients predisposed to such disorders, and including exacerbation of these symptoms if present)
Nervous system disorders
Uncommon: headache, dizziness
Rare: taste disturbances
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
Not known: microscopic colitis
Hepatobiliary disorders
Uncommon: increased liver enzymes (transaminases, γ-GT)
Rare: increased bilirubin levels
Not known: hepatocellular injury, jaundice, hepatocellular failure
Skin and subcutaneous tissue disorders
Uncommon: skin rashes, exanthema, pruritus
Rare: urticaria, angioneurotic edema
Not known: Stevens-Johnson syndrome, Lyell’s syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus
Musculoskeletal and connective tissue disorders
Uncommon: fractures of the femur, wrist, spine (see section "Special precautions")
Rare: arthralgia, myalgia
Not known: muscle spasms2
Renal and urinary disorders
Not known: interstitial nephritis (with possible development of renal failure)
Reproductive system and breast disorders
Rare: gynecomastia
General disorders and administration site conditions
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.
Shelf life. 2 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.
Incompatibilities.
Sodium pantoprazole is incompatible with acidic solutions.
Pantoprazole must not be prepared or mixed with solvents other than those specified in the section "Dosage and administration".
Packaging.
40 mg in a vial. Packaged as 1 vial in a cardboard box or 5 vials in a blister pack, with 1 blister pack in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
LLC "FARMEX GROUP"
Manufacturer's address and place of business.
100 Shevchenka Street, Boryspil, Kyiv Oblast, Ukraine, 08301