Proxium

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PROXIUM® (PROXIUM®)

Composition:

Active substance: pantoprazole;

One tablet contains pantoprazole sodium sesquihydrate equivalent to 40 mg of pantoprazole;

Excipients: sodium carbonate anhydrous, mannitol (E 421), sodium croscarmellose, sodium starch glycolate (type A), magnesium stearate, colloidal anhydrous silicon dioxide;

Coating composition: propylene glycol, yellow iron oxide (E 172), titanium dioxide (E 171), hypromellose, triethyl citrate, methacrylate copolymer (type A).

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties: oval, biconvex orange-colored tablets coated with an enteric coating.

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 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, thereby blocking the final step of gastric acid production. Inhibition is dose-dependent and affects both basal and stimulated acid secretion. Most patients are relieved of symptoms within 2 weeks. As with other proton pump inhibitors and H2-receptor antagonists, pantoprazole reduces gastric acidity and thereby 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 gastric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect of oral and intravenous administration of the drug is equivalent.

With pantoprazole use, fasting gastrin levels increase. With short-term use, these levels usually do not exceed the upper limit of normal. With long-term treatment, gastrin levels typically double. Marked elevation occurs only in isolated cases. As a consequence, in a small number of cases during prolonged treatment, mild or moderate increase in specific enterochromaffin-like (ECL) cells in the stomach (similar to adenomatoid hyperplasia) may be observed. However, according to studies conducted to date, the development of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors, as observed in animal studies, has not been observed in humans.

Based on animal studies, the influence of long-term (more than 1 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 reduced gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may interfere with diagnostic test results for neuroendocrine tumors. Available published data indicate that proton pump inhibitor therapy should be discontinued for a period of 5 days to 2 weeks prior to CgA level measurements. This allows CgA levels to return to the normal range, as they may be falsely elevated after PPI treatment.

Pharmacokinetics.

Absorption. Pantoprazole is rapidly absorbed, and maximum plasma concentrations are achieved after a single 40 mg oral dose. On average, peak serum concentration of about 2–3 µg/mL is reached within 2.5 hours after administration; concentrations remain stable after repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. Within the dose range of 10 to 80 mg, pantoprazole pharmacokinetics in plasma remain linear for both oral and intravenous administration. Absolute bioavailability of tablets is approximately 77%. Concomitant food intake does not affect AUC (area under the concentration-time curve) or peak serum concentration, and thus does not affect bioavailability. Food intake only increases the variability of the lag time.

Distribution. Pantoprazole protein binding in plasma is approximately 98%. The volume of distribution is about 0.15 L/kg.

Metabolism. The substance is almost exclusively metabolized in the liver. The main metabolic pathway is demethylation via CYP2C19, followed by sulfation; 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 noted. 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 (about 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; these individuals are referred to as poor metabolizers. In these individuals, pantoprazole metabolism is likely primarily catalyzed by CYP3A4. After a single 40 mg dose, 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 findings do not affect pantoprazole dosing.

Renal impairment. No dose adjustment recommendations are required when prescribing pantoprazole to patients with impaired renal function (including dialysis patients). 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, 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, peak 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 ones is also not clinically significant.

Children. After single oral doses of 20 or 40 mg pantoprazole, AUC and Cmax in children aged 5 to 16 years were within the range of corresponding values in adults. 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 age or body weight was observed. AUC and volume of distribution corresponded to data obtained in adult studies.

Clinical characteristics.

Indications.

Adults and children aged 12 years and older.

• Gastroesophageal reflux disease (GERD) with erosive esophagitis.

Adults only.

• Eradication of Helicobacter pylori (H. pylori) in patients with H. pylori-associated gastric and duodenal ulcers, in combination with appropriate antibiotics.
• Duodenal ulcer.
• Gastric ulcer.
• Zollinger-Ellison syndrome and other hypersecretory conditions.

Contraindications. Hypersensitivity to the active substance, benzimidazole derivatives, or any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Medicinal products whose absorption is pH-dependent. Due to complete and prolonged inhibition of gastric acid secretion, pantoprazole may affect the absorption of drugs for which gastric pH is an important factor in 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 is dependent on intragastric pH, is not recommended due to a significant reduction in their bioavailability (see section "Special precautions").

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 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 receiving PPIs concomitantly with warfarin or phenprocoumon. Increased INR and prolonged prothombin 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 that concomitant administration 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 those with cancer or psoriasis, should temporarily discontinue pantoprazole therapy.

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 and other pathways. Studies with medicinal products that are also metabolized via these pathways—such as carbamazepine, diazepam, glyburide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—have not revealed clinically significant interactions.

Interactions between pantoprazole and other drugs metabolized by 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), nor does it affect P-glycoprotein involved in digoxin absorption.

No interaction has been observed with concomitantly administered antacids.

Studies investigating the interaction between pantoprazole and concomitantly administered antibiotics (clarithromycin, metronidazole, amoxicillin) have not revealed any clinically significant interactions.

Medicinal products that inhibit or induce CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, may increase the systemic exposure to pantoprazole. Consideration should be given to reducing the dose in patients receiving 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.

Interaction between medicinal products and laboratory tests. False-positive results in certain urine screening tests for tetrahydrocannabinol (THC) have been reported in patients taking pantoprazole. Alternative confirmatory testing methods should be considered to verify positive results.

Special precautions for use.

Hepatic impairment. Patients with severe impairment of liver function should have regular monitoring of liver enzymes, especially during long-term treatment. If liver enzyme levels increase, treatment with the drug must be discontinued (see section "Dosage and administration").

Combination therapy. During combination therapy, the instructions for medical use of the respective medicinal products must be followed.

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 in suspected or confirmed gastric ulcer, malignancy must be ruled out.

If symptoms persist despite adequate treatment, further investigations are required.

HIV protease inhibitors. Concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir), whose absorption is pH-dependent, is not recommended due to a significant reduction in their 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 or risk factors for reduced vitamin B12 absorption during prolonged therapy, or in the presence of relevant clinical symptoms.

Long-term treatment. Patients undergoing long-term treatment, particularly longer than 1 year, should be under regular medical supervision.

Gastrointestinal infections caused by bacteria. Treatment with Proxium® may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile.

Hypomagnesemia. Cases of severe hypomagnesemia have been observed in patients treated with proton pump inhibitors (PPIs), such as pantoprazole, for at least 3 months, and in most cases after one year. Serious clinical manifestations of hypomagnesemia, which may develop initially unnoticed, include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. 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), patients' condition usually improved after magnesium replacement therapy and discontinuation of PPI treatment.

Patients requiring long-term therapy, or those taking PPIs concomitantly with digoxin or medications that may cause hypomagnesemia (e.g., diuretics), should have serum magnesium levels measured before starting PPI treatment and periodically during treatment.

Bone fractures. Long-term (more than 1 year) high-dose treatment with proton pump inhibitors may moderately increase the risk of fractures of the hip, wrist, and spine, particularly in elderly patients or those with other risk factors. Observational studies suggest that the use of proton pump inhibitors 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 should consume adequate amounts of vitamin D and calcium.

Severe cutaneous adverse reactions. Severe cutaneous adverse reactions, with unknown frequency, associated with the use of pantoprazole have been reported (see section "Adverse reactions"), which may be life-threatening or fatal, such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Patients should be informed about the signs and symptoms of these skin reactions, and closely monitored for their development. If signs or 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, particularly in sun-exposed areas, accompanied by arthralgia, the patient should seek immediate medical advice, and discontinuation of Proxium® should be considered. Development of subacute cutaneous lupus erythematosus in patients during prior therapy with proton pump inhibitors may increase the risk of recurrence with other proton pump inhibitors.

Effect on laboratory test results.

Elevated chromogranin A (CgA) levels may interfere with diagnostic tests for neuroendocrine tumors. To avoid this interference, treatment with Proxium® 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 proton pump inhibitor therapy.

Sodium. Proxium® contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. Available data on the use of pantoprazole in pregnant women (approximately 300–1000 reports on pregnancy outcomes) indicate no embryonal or fetal/neonatal toxicity of pantoprazole. Reproductive toxicity was observed in animal studies. As a precautionary measure, use of Proxium® 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 Proxium® should be made taking into account the benefit of breastfeeding for the child and the benefit of treatment with Proxium® 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 considered (see section "Adverse reactions"). In such cases, patients should not drive or operate machinery.

Dosage and Administration

Proxium®, enteric-coated tablets, should be taken whole, one hour before a meal. Do not chew or crush the tablets. Swallow with water.

Recommended dosage.

Adults and children aged 12 years and older.

Treatment of reflux esophagitis.

The recommended dose is 1 tablet of Proxium® 40 mg once daily. In some cases, the dose may be doubled (2 tablets of Proxium® 40 mg daily), especially if there is no response to other treatments for reflux esophagitis. Treatment of reflux esophagitis usually requires 4 weeks. If this is insufficient, healing may be expected within the following 4 weeks.

Adults.

Eradication of H. pylori in combination with two antibiotics.

In adult patients with gastric or duodenal ulcers and a positive H. pylori test, eradication of the organism should be achieved using combination therapy. Local data on bacterial resistance and national guidelines for appropriate antibiotic use should be considered. Depending on susceptibility, the following treatment regimens may be used for H. pylori eradication in adults:

a) 1 tablet of Proxium® 40 mg twice daily

• 1000 mg amoxicillin twice daily
• 500 mg clarithromycin twice daily;

b) 1 tablet of Proxium® 40 mg twice daily

• 400–500 mg metronidazole (or 500 mg tinidazole) twice daily
• 250–500 mg clarithromycin twice daily;

c) 1 tablet of Proxium® 40 mg twice daily

• 1000 mg amoxicillin twice daily
• 400–500 mg metronidazole (or 500 mg tinidazole) twice daily.

When using combination therapy for H. pylori eradication, the second dose of Proxium® 40 mg should be taken in the evening, one hour before a meal. The treatment duration is 7 days and may be extended for another 7 days, with a total treatment period not exceeding 2 weeks. If further treatment with pantoprazole is indicated to ensure ulcer healing, refer to dosage recommendations for gastric and duodenal ulcers. If combination therapy is not indicated, e.g., in patients with a negative H. pylori test, monotherapy with Proxium® 40 mg should be administered according to the dosage recommendations below.

Treatment of gastric ulcer.

1 tablet of Proxium® 40 mg once daily. In some cases, the dose may be doubled (2 tablets of Proxium® 40 mg daily), especially if there is no response to other treatments.

Treatment of gastric ulcer usually requires 4 weeks. If this is insufficient, ulcer healing may be expected within the following 4 weeks.

Treatment of duodenal ulcer.

1 tablet of Proxium® 40 mg once daily. In some cases, the dose may be doubled (2 tablets of Proxium® 40 mg daily), especially if there is no response to other treatments.

Treatment of duodenal ulcer usually requires 2 weeks. If this is insufficient, ulcer healing may be expected within the following 2 weeks.

Treatment of Zollinger–Ellison syndrome and other hypersecretory conditions.

For long-term treatment of Zollinger–Ellison syndrome and other hypersecretory conditions, the initial daily dose is 80 mg (2 tablets of Proxium® 40 mg). If necessary, the dose may be titrated thereafter, either increased or decreased, based on gastric acid secretion parameters. Doses exceeding 80 mg daily should be divided into two doses. Temporary dose increases above 160 mg of pantoprazole may be possible, but the duration of such high-dose therapy should be limited to the period required for adequate acid control.

The duration of treatment for Zollinger–Ellison syndrome and other hypersecretory conditions is not limited and depends on clinical necessity.

Patients with hepatic impairment. In patients with severe liver dysfunction, the daily dose should not exceed 20 mg (1 tablet of Proxium® 20 mg). Proxium® should not be used for H. pylori eradication in combination therapy in patients with moderate to severe hepatic impairment, as there are currently no data on the efficacy and safety of such use in this patient group.

Patients with renal impairment. Dose adjustment is not required in patients with impaired renal function. Proxium® should not be used for H. pylori eradication in combination therapy in patients with renal impairment, as there are currently no data on the efficacy and safety of such use in this patient group.

Elderly patients do not require dose adjustment.

Children. Proxium® 40 mg is indicated in children aged 12 years and older for the treatment of reflux esophagitis. The drug is not recommended for children under 12 years of age, as data on safety and efficacy in this age group are limited.

Overdose.

Symptoms of overdose are unknown.

Doses up to 240 mg administered intravenously over 2 minutes were well tolerated. Since pantoprazole is highly 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 specific antidotes or recommended specific treatments.

Adverse Reactions

Adverse reactions were observed in approximately 5% of patients. The most common adverse reactions were diarrhea and headache (occurring in about 1% of patients).

Undesirable effects 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 (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), and not known (frequency cannot be estimated from available data).

For all adverse reactions reported during the post-marketing period, the frequency cannot be determined; therefore, they are listed as "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
Not known: hyponatremia, hypomagnesemia (see section "Special precautions for use"), hypocalcemia¹, hypokalemia¹

Psychiatric disorders

Uncommon: sleep disorders
Rare: depression (including exacerbation)
Very rare: confusion (including exacerbation)
Not known: hallucination, confusion (particularly in patients predisposed to such disorders, and exacerbation of these symptoms if pre-existing)

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, bloating, 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
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 (toxic epidermal necrolysis), 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
Not known: muscle spasms²

Renal and urinary disorders

Not known: tubulointerstitial nephritis (with possible progression to renal failure)

Reproductive system and breast disorders

Rare: gynecomastia

General disorders

Uncommon: asthenia, fatigue, malaise
Rare: increased body temperature, peripheral edema

¹ Hypocalcemia and/or hypokalemia may be associated with the development of hypomagnesemia (see section "Special precautions for use").
² Muscle spasms as a consequence of electrolyte imbalance.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system (https://aisf.dec.gov.ua).

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep in the original packaging, in a place inaccessible to children.

Packaging. 8 tablets in a blister pack, 4 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Laboratorios Normon S.A.

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