Espa-prazole®

Pharmaceutical form. Gastro-resistant tablets.

Main physicochemical properties: yellow, oval-shaped tablets.

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 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 become symptom-free within 2 weeks. The use of pantoprazole, as with other proton pump inhibitors (PPIs) and H₂-receptor antagonists, reduces gastric acidity and thereby increases gastrin secretion proportionally to the reduction 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 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 in most cases double. However, excessive increases occur only in isolated cases. As a consequence, mild or moderate increase in specific endocrine (ECL) cells in the stomach (similar to adenomatoid hyperplasia) may occasionally be observed during long-term treatment. However, according to studies conducted to date, the formation of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors, which were observed in animal studies, 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 completely ruled out.

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 treatment with proton pump inhibitors should be discontinued 5–14 days before measuring CgA levels. This allows CgA levels to return to the normal range, which may be falsely elevated after PPI treatment.

Pharmacokinetics.

Absorption. Pantoprazole is rapidly absorbed, and maximum plasma concentration is achieved after a single oral dose of 20 mg. On average, maximum serum concentration of about 1–1.5 µg/mL is reached within 2–2.5 hours after administration; concentration remains stable after repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. In 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 maximum serum concentration, and thus does not affect bioavailability. Only the variability of the latent period increases when taken with food.

Distribution. Pantoprazole protein binding in serum is about 98%. Volume of distribution is approximately 0.15 L/kg.

Biotransformation. The substance is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation via CYP2C19 followed by sulfate conjugation; other metabolic pathways include oxidation via CYP3A4.

Elimination. 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 in parietal cells, the elimination half-life does not correspond to the much longer duration of action (acid secretion inhibition).

The majority of pantoprazole metabolites are excreted in urine (about 80%), the remainder 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 average 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 average peak plasma concentration increased by approximately 60%. These results do not affect pantoprazole dosing.

Renal impairment. No dosage recommendations for reducing the dose when prescribing pantoprazole to patients with impaired renal function (including dialysis patients) are required. As in healthy individuals, the elimination half-life of pantoprazole in these patients 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 impairment. Although in patients with liver cirrhosis (Child-Pugh classes A and B) the half-life increases to 3–6 hours and AUC increases 3–5 times, maximum serum concentration increases only slightly—by 1.3 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 oral dose of 20 or 40 mg of pantoprazole, AUC and Cmax in children aged 5 to 16 years were within the corresponding values in adults. 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 correlation between pantoprazole clearance and patient age or body weight was observed. AUC and volume of distribution corresponded to data obtained in adult studies.

Clinical characteristics.

Indications.

Adults and children aged 12 years and older.

• Symptomatic treatment of gastroesophageal reflux disease.
• Long-term treatment and prevention of relapses of reflux esophagitis.

Adults.

• Prevention of gastric and duodenal ulcers caused by non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in high-risk patients who need to take NSAIDs long-term.

Contraindications. Hypersensitivity to the active substance, benzimidazole derivatives, or any excipient of the drug.

Interaction with other medicinal products and other forms of interaction.

Drugs whose absorption depends on pH. Due to complete and prolonged inhibition of hydrochloric acid secretion, pantoprazole may affect the absorption of drugs for which gastric juice pH is an important factor for their bioavailability (e.g., certain antifungal agents such as ketoconazole, itraconazole, posaconazole, or other drugs such as erlotinib).

HIV protease inhibitors. Concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir), whose absorption depends on intragastric pH, is not recommended due to significant reduction in their bioavailability (see section "Special precautions for use").

In cases where 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, 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. In such cases of concomitant use, monitoring of INR and prothrombin time is necessary.

Methotrexate. Concurrent use of high-dose methotrexate (e.g., 300 mg) and proton pump inhibitors has been reported to increase methotrexate blood levels in some patients. Patients taking high doses of methotrexate, such as cancer or psoriasis patients, are advised 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, glyburide, nifedipine, and oral contraceptives containing levonorgestrel and ethinyl estradiol, did not reveal clinically significant interactions.

Interaction of pantoprazole with other drugs metabolized via the same enzyme system cannot be excluded.

Results of numerous 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 with concomitantly administered antacids has been observed.

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

Drugs that inhibit or induce CYP2C19. CYP2C19 inhibitors, such as fluvoxamine, may increase systemic exposure to pantoprazole. Dose reduction should be considered for patients on long-term high-dose pantoprazole therapy and for patients with hepatic impairment. Enzyme inducers affecting CYP2C19 and CYP3A4, such as rifampicin and St. John's wort (Hypericum perforatum), may reduce plasma concentrations of PPIs metabolized via these enzyme systems.

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 results.

Special precautions for use.

Hepatic impairment. In patients with severe hepatic impairment, liver enzyme levels should be regularly monitored, especially during long-term treatment. If liver enzyme levels increase, treatment with the drug should be discontinued (see section "Dosage and administration").

Concomitant use with NSAIDs. The drug Espa-prazole®, 20 mg tablets, should be used for prevention of gastric and duodenal ulcers due to long-term NSAID use only in patients prone to frequent recurrences of gastric and duodenal ulcers.

Risk assessment is based on individual factors, including age (>65 years), history of gastric or duodenal ulcer, and gastrointestinal bleeding.

Gastric malignancies. Symptomatic response to pantoprazole may mask symptoms of gastric malignancies and delay their diagnosis. In case of alarm symptoms (e.g., significant weight loss, recurrent vomiting, dysphagia, vomiting blood, anemia, melena), and in the presence of gastric ulcer or suspicion thereof, gastric malignancy must be ruled out.

If symptoms persist despite adequate treatment, further investigation is necessary.

HIV protease inhibitors. Concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir), whose absorption depends on intragastric pH, is not recommended due to significant reduction in their bioavailability (see section "Interaction with other medicinal products and other forms of interaction").

Vitamin B12 absorption. Pantoprazole may reduce vitamin B12 (cyanocobalamin) absorption due to hypochlorhydria or achlorhydria. This should be considered in case of low body weight or factors reducing vitamin B12 absorption during long-term treatment, or presence of relevant clinical symptoms.

Long-term treatment. During long-term treatment, especially longer than 1 year, patients should be under regular medical supervision.

Gastrointestinal infections caused by bacteria. Treatment with Espa-prazole® slightly increases the risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or C. difficile.

Hypomagnesemia. Rare cases of severe hypomagnesemia have been observed in patients receiving PPIs, such as pantoprazole, for at least three months, mostly after one year. Serious clinical manifestations of hypomagnesemia, such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia, may develop insidiously. Hypomagnesemia may lead to 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 PPIs.

In patients requiring long-term therapy and in 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 treatment (more than 1 year) with high doses of proton pump inhibitors moderately increases the risk of hip, wrist, and spine fractures, primarily in elderly individuals or those with other risk factors. Observational studies indicate that PPI use increases the overall fracture risk by 10–40%. Some of these may be due to other risk factors. Patients at risk of osteoporosis should receive treatment according to current clinical guidelines and consume adequate vitamin D and calcium.

Severe skin adverse reactions. Severe skin adverse reactions associated with pantoprazole use, which may be life-threatening or fatal, including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported. The frequency of these reactions is unknown (see section "Adverse reactions"). Patients should be informed of signs and symptoms and closely monitored. If symptoms indicating these reactions occur, pantoprazole use should be immediately discontinued 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, especially in sun-exposed areas, accompanied by arthralgia, occur, the patient should immediately consult a physician who will consider discontinuing Espa-prazole®. Development of subacute cutaneous lupus erythematosus in patients during previous therapy with proton pump inhibitors increases the risk of its development when using other proton pump inhibitors.

Effect on laboratory test results. Elevated chromogranin A (CgA) levels may affect test results when diagnosing neuroendocrine tumors. To avoid this effect, Espa-prazole® treatment should be temporarily discontinued at least 5 days before CgA level assessment (see section "Pharmacodynamics"). If CgA and gastrin levels do not return to normal range after initial measurement, repeat measurements should be performed 14 days after discontinuation of proton pump inhibitor therapy.

Sodium. The drug 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 Espa-prazole® in pregnant women (approximately 300–1000 pregnancy outcomes) indicate no embryonal or fetoneonatal toxicity of the drug. Reproductive toxicity was observed in animal studies. As a precautionary measure, use of Espa-prazole® in pregnant women should be avoided.

Breastfeeding. Animal studies showed excretion of pantoprazole in breast milk. Data on excretion of pantoprazole in human breast milk are limited, but such excretion has been reported. Risk to newborns/infants cannot be excluded. The decision to discontinue breastfeeding or to discontinue/abstain from Espa-prazole® treatment should be made considering the benefit of breastfeeding for the child and the benefit of Espa-prazole® treatment for the woman.

Fertility. Pantoprazole did not impair fertility in animal studies.

Ability to affect reaction rate when driving or operating machinery. Pantoprazole has no effect or a very minor effect on reaction rate when driving or operating machinery. Possible development of adverse reactions such as dizziness and visual disturbances should be considered (see section "Adverse reactions"). In such cases, driving or operating machinery should be avoided.

Method of administration and dosage.

Esppa-prazole®, gastro-resistant tablets, should be taken whole, 1 hour before meals, without chewing or crushing, with water.

Adults and children aged 12 years and older.

Symptomatic treatment of gastroesophageal reflux disease.

The recommended dose is 20 mg (1 tablet) of Espa-prazole® once daily. Heartburn symptoms usually resolve within 2–4 weeks. If this period is insufficient, treatment may be continued for another 4 weeks. After symptom resolution, recurrence of symptoms can be managed as needed with 20 mg of the drug (1 tablet) once daily. Transition to long-term therapy should be considered if adequate symptom control is not achieved with on-demand therapy.

Long-term treatment and prevention of reflux esophagitis relapses.

For long-term maintenance therapy, the dose is 20 mg (1 tablet) of Espa-prazole® once daily. During disease exacerbation, the dose may be increased to 40 mg daily. In such cases, Espa-prazole® 40 mg tablets are recommended. After resolution of relapse, the dose may be reduced again to 20 mg daily.

Adults.

Prevention of gastric and duodenal ulcers caused by non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in high-risk patients who need to take NSAIDs long-term.

The recommended dose is 20 mg (1 tablet) of Espa-prazole® once daily.

Hepatic impairment. Patients with severe hepatic impairment should not exceed a dose of 20 mg (1 tablet) daily.

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

Elderly patients do not require dose adjustment.

Children. The drug is not recommended for children under 12 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 does not belong to drugs that can be easily removed by dialysis.

In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy should be applied. No recommendations for specific therapy are available.

Adverse reactions.

Adverse reactions may be expected in about 5% of patients. The most common adverse reactions are diarrhea and headache (occurring in about 1% of patients).

Adverse effects are classified by frequency 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), unknown (frequency cannot be estimated from available data).

For all adverse reactions reported during the post-marketing period, frequency cannot be determined and is therefore listed as "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), weight changes.

Unknown: hyponatremia, hypomagnesemia (see section "Special precautions for use"), hypocalcemia¹, hypokalemia.

Psychiatric disorders.

Uncommon: sleep disorders.

Rare: depression (including worsening).

Very rare: disorientation (including worsening).

Unknown: hallucinations, confusion (especially in patients predisposed to such disorders, and worsening of these symptoms if pre-existing).

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 disorders.

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

Rare: increased bilirubin levels.

Unknown: hepatocyte injury, jaundice, hepatocellular failure.

Skin and subcutaneous tissue disorders.

Uncommon: skin rashes, exanthema, pruritus.

Rare: urticaria, angioedema.

Unknown: Stevens-Johnson syndrome, Lyell's 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: hip, wrist, spine fractures (see section "Special precautions for use").

Rare: arthralgia, myalgia.

Unknown: muscle spasms².

Renal and urinary disorders.

Unknown: interstitial nephritis (with possible development of 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 hypomagnesemia (see section "Special precautions for use").

² Muscle spasms as a result of electrolyte imbalance.

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is of great importance. This allows monitoring of the benefit-risk ratio of this drug. 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 (https://aisf.dec.gov.ua).

Shelf life. Aluminum foil blisters on both sides — 60 months.

Aluminum foil blister on one side and PVC/PE/PVdC film on the other — 30 months.

Storage conditions. Store in original packaging at a temperature not exceeding 25°C. Keep out of reach of children!

Packaging. 14 tablets in a blister (aluminum foil on both sides or aluminum foil on one side and PVC/PE/PVdC film on the other), 1 or 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Advanz Pharma GmbH, Germany.

Manufacturer's address. Wallenroder Strasse 12–14, 13435 Berlin, Germany.