Proxium pro

INSTRUCTION
for medical use of medicinal product

PROXIUM PRO
(PROXIUM PRO)

Pharmaceutical form. Powder for solution for injection.

Basic physicochemical properties: white or almost white porous lyophilized powder.

Pharmacotherapeutic group. Drugs for treatment of acid-related disorders. 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 hydrochloric acid production in the stomach. 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. Increased 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 equivalent.

Administration of pantoprazole increases fasting gastrin levels. With short-term use of the drug, gastrin levels usually do not exceed the upper limit of normal. With long-term treatment, gastrin levels increase approximately twofold in most cases. Excessive increases, however, occur extremely rarely. As a consequence, mild or moderate increase in the number of enterochromaffin-like cells (ECL cells) in the stomach (similar to adenomatoid hyperplasia) may be observed in some cases during long-term treatment. However, according to study data, the formation of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors, which were observed in animal experiments, has not been observed in humans.

Based on animal studies, a long-term (more than one year) effect of 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. In addition, due to reduced gastric acidity, chromogranin A (CgA) levels increase. 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 to return to normal ranges, which may be falsely elevated after PPI treatment.

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 serum 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 via CYP2C19 with subsequent sulfation conjugation; other metabolic pathways include oxidation via 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) slightly exceeds that of pantoprazole.

Special patient groups

Slow metabolizers. About 3% of Europeans have low functional activity of the CYP2C19 enzyme; they are called slow 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 was approximately 6 times higher in slow metabolizers than in individuals with functionally active CYP2C19 (fast metabolizers). The mean peak plasma concentration increased by about 60%. These results do not affect pantoprazole dosing.

Renal function impairment. There are no recommendations for dose reduction when prescribing pantoprazole to patients with impaired renal function (including dialysis patients). As in healthy individuals, the half-life of pantoprazole in them is short. Only very small amounts of pantoprazole are dialyzed. Despite the moderately prolonged half-life (2–3 hours) of the main metabolite, elimination is still rapid, so accumulation does not occur.

Hepatic function 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 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 found between pantoprazole clearance and patient age or body weight. AUC and volume of distribution corresponded to data obtained in adult studies.

Clinical characteristics.

Indications.

The medicinal product is indicated for use in adults for:

• reflux esophagitis,
• gastric and duodenal ulcer,
• 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 types of interactions.

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 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").

In cases where 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 required.

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, increased INR and prolonged prothrombin time have been reported 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 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, such as cancer or psoriasis patients, are recommended to temporarily discontinue pantoprazole treatment.

Other interactions. Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation via CYP2C19 and other metabolic pathways, including oxidation via CYP3A4. Studies with drugs also metabolized via these pathways, such as carbamazepine, diazepam, glibenclamide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol, did not reveal clinically significant interactions.

Interaction of pantoprazole with 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 have been conducted on the interaction of pantoprazole with concomitantly administered certain antibiotics (clarithromycin, metronidazole, amoxicillin). No clinically significant interactions between these drugs were found.

Drugs that inhibit or induce CYP2C19. CYP2C19 inhibitors, such as fluvoxamine, may increase the systemic effect of pantoprazole. Consideration should be given to reducing the dose of CYP2C9 inhibitors for patients receiving long-term pantoprazole therapy at high doses and for 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 have been reported in patients taking pantoprazole. Alternative testing methods should be considered to confirm positive results.

Special precautions for use.

Malignant gastric tumors. 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 suspicion or presence of gastric ulcer, the presence of a malignant process must be excluded.

If symptoms persist during adequate treatment, additional examination is required.

Hepatic function impairment. In patients with severe hepatic function impairment, liver enzyme levels should be monitored regularly. If liver enzyme levels increase, treatment with the drug should be discontinued (see section "Dosage and method of 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 the drug may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or C. difficile.

Hypomagnesemia. Cases of severe hypomagnesemia have been reported in patients receiving PPIs, such as pantoprazole, for at least three months, and in most cases for a year. Serious clinical manifestations of hypomagnesemia, which may initially be unnoticed and gradually develop, include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia. Hypomagnesemia may lead to the development of hypocalcemia and/or hypokalemia (see section "Adverse reactions"). In cases of hypomagnesemia (and hypocalcemia and/or hypokalemia associated with hypomagnesemia), the condition of most patients improved after replacement corrective therapy with magnesium and discontinuation of PPIs.

In patients requiring long-term therapy and patients taking PPIs concomitantly with digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), magnesium levels should be determined before starting PPI therapy and periodically during treatment.

Bone fractures. Long-term (more than 1 year) high-dose PPI treatment may moderately increase the risk of hip, wrist, and spine fractures, primarily in elderly individuals or those with other risk factors. Observational studies indicate that PPI use may increase the overall fracture risk 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.

Severe skin adverse reactions. Severe skin adverse reactions associated with pantoprazole use, with unknown frequency of occurrence (see section "Adverse reactions"), potentially life-threatening or fatal, such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported. Patients should be informed about the signs and symptoms of these skin reactions and carefully monitored for their development. If signs and symptoms indicating these reactions appear, pantoprazole use should be immediately discontinued and alternative treatment considered.

Subacute cutaneous lupus erythematosus. PPI use has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions, especially in sun-exposed areas, occur and are accompanied by arthralgia, the patient should immediately consult a physician who will consider the necessity of discontinuing the drug. Development of subacute cutaneous lupus erythematosus in patients during previous PPI therapy may increase the risk of its development when using other PPIs.

Effect on laboratory test results. Elevated chromogranin A (CgA) levels may affect test results when diagnosing neuroendocrine tumors. To avoid such influence, drug treatment should be temporarily discontinued at least 5 days before assessing CgA levels (see section "Pharmacodynamics"). If CgA and gastrin levels do not return to normal ranges after initial measurement, repeat measurements should be performed 14 days after discontinuation of PPI treatment.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. Available data on the use of pantoprazole in pregnant women (approximately 300–1000 pregnancy outcomes) indicate the absence of embryonal or fetal/neonatal toxicity of pantoprazole. Reproductive toxicity was observed in animal studies. As a precaution, the use of the drug in pregnant women should be avoided.

Breastfeeding. In animal studies, excretion of pantoprazole in breast milk was detected. There is insufficient data on the 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 drug treatment should be made considering the benefit of breastfeeding for the child and the benefit of drug 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 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 not be performed.

Dosage and method of administration

The medicinal product should be used 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 the duration of intravenous treatment up to 7 days. Therefore, as soon as oral administration of pantoprazole becomes possible, transition from intravenous to oral administration of pantoprazole at a dose of 40 mg should be made.

Reflux esophagitis, duodenal ulcer, gastric ulcer.

The recommended dose is 40 mg pantoprazole (1 vial) daily intravenously.

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 is 80 mg daily. If necessary, the dose can be titrated, increased or decreased, depending on gastric acid secretion parameters. Doses exceeding 80 mg daily must be divided into two administrations. Temporary increase in pantoprazole dose to more than 160 mg is possible, but the 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.

Hepatic impairment. Patients with severe hepatic function impairment should not exceed a daily dose of 20 mg (½ vial of Proxium Pro) (see section "Special precautions for use").

Renal impairment. Patients with impaired renal function do not require dose adjustment.

Elderly patients do not require dose adjustment.

Preparation for use

Dissolve the powder in 10 ml of 0.9% sodium chloride solution added to the vial immediately before use. 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 bottles.

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.

Proxium Pro must not be 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. Residual drug or drug with altered physicochemical properties (e.g., color change, sediment formation) must be disposed of according to current legislation.

The diluted solution should have a clear yellowish color.

Children.

Proxium Pro, 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 of the drug in this age group. Available data are presented 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 administered. There are no recommendations for specific therapy.

Adverse reactions.

Adverse reactions may be expected in about 5% of patients.

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).

For all adverse reactions reported during the post-marketing period, frequency cannot be determined; therefore, they are listed with the frequency "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"), hypocalcemia¹, hypokalemia¹.

Psychiatric disorders.

Uncommon: sleep disorders.

Rare: depression (including exacerbation).

Very rare: disorientation (including exacerbation).

Unknown: hallucinations, confusion (especially in patients predisposed to such disorders, and exacerbation of these symptoms if previously present).

Nervous system disorders.

Uncommon: headache, dizziness.

Rare: taste disturbances.

Unknown: paresthesia.

Eye disorders.

Rare: visual disturbances / blurred vision.

Gastrointestinal disorders.

Common: fundic gland polyps (benign).

Uncommon: diarrhea, nausea, vomiting, bloating, constipation, dry mouth, abdominal pain and discomfort.

Unknown: microscopic colitis.

Hepatobiliary system disorders.

Uncommon: increased liver enzymes (transaminases, γ-glutamyltransferase).

Rare: increased bilirubin levels.

Unknown: hepatocyte injury, jaundice, hepatocellular insufficiency.

Skin and subcutaneous tissue disorders.

Uncommon: skin rashes, exanthema, pruritus.

Rare: urticaria, angioedema.

Unknown: Stevens-Johnson syndrome, Lyell syndrome (toxic epidermal necrolysis), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), 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 spasms².

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, 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.

Reporting of adverse reactions after drug registration is important. This allows monitoring of the benefit-risk ratio of this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

From a microbiological point of view, the diluted drug must be used immediately. However, the physicochemical stability of the diluted drug is maintained for 12 hours at 25 °C. After dilution, the shelf life of the ready solution is 12 hours.

Storage conditions. Store in original packaging at a temperature not exceeding 30 °C, in a place inaccessible to children.

Packaging. 1 vial in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Laboratorios Normon S.A.

Manufacturer's location and address of business activity. Ronda de Valdecarrizo, 6, Tres Cantos, 28760 Madrid, Spain.

Yes