Ulsipan

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ULSIPAN (ULSEPAN)

Composition:

Active substance: pantoprazole;

One enteric-coated tablet contains 40 mg of pantoprazole (as sodium pantoprazole sesquihydrate);

Excipients:

Core: mannite (E 421), calcium carbonate, crospovidone, povidone, sucrose stearate, calcium stearate;

Film coating: Opadry White YS-1-70277 (hypromellose, titanium dioxide (E 171), glycerol triacetate);

Enteric coating: Acryl-Eze Yellow 93092157 (methacrylate copolymer (type C), talc, titanium dioxide (E 171), triethyl citrate, anhydrous colloidal silicon dioxide, sodium bicarbonate, iron oxide yellow (E 172), sodium lauryl sulfate).

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties: yellow, oval, biconvex tablets coated with a film.

Pharmacotherapeutic group.

Drugs for treatment of acid-related disorders. Proton pump inhibitors. ATC code A02BC02.

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 H⁺-K⁺-ATPase enzyme, thereby blocking the final step of gastric hydrochloric acid production. The inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. In most patients, symptoms resolve within 2 weeks. The use of pantoprazole, as well as other proton pump inhibitors (PPIs) and H₂-histamine receptor antagonists, reduces gastric acidity and consequently increases gastrin secretion proportionally to the decrease in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds the enzyme distal to the cellular receptor, it can inhibit hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect of pantoprazole is the same following oral and intravenous administration.

Administration of pantoprazole increases fasting gastrin levels. With short-term use, gastrin levels usually do not exceed the upper limit of normal; with long-term use, levels typically double. However, excessive elevation occurs only in isolated cases. As a result, in a small number of patients on long-term pantoprazole therapy, mild or moderate increases in the number of enterochromaffin-like (ECL) cells in the stomach (similar to adenomatoid hyperplasia) may be observed. However, according to available studies, the formation of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors, which were observed in animal experiments, has not been reported in humans.

Based on animal studies, the influence of long-term (more than one year) pantoprazole use on thyroid gland endocrine parameters cannot be excluded.

During treatment with antisecretory agents, plasma 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 PPI treatment should be discontinued 5 days to 2 weeks before measuring CgA levels. This allows CgA levels to return to the normal range, as they may be falsely elevated after PPI therapy.

Pharmacokinetics.

Absorption.

Pantoprazole is rapidly absorbed, and maximum plasma concentration (C_max) is achieved after a single oral dose of 40 mg. On average, C_max of approximately 2–3 μg/mL is reached within 2.5 hours after administration; the concentration remains consistent with repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. When pantoprazole is administered at doses of 10–80 mg, its pharmacokinetics 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 C_max, and thus does not affect bioavailability. However, food intake slightly increases the variability of the latency period.

Distribution.

Plasma protein binding of pantoprazole is approximately 98%. The volume of distribution is about 0.15 L/kg.

Metabolism.

Pantoprazole is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation via CYP2C19, followed by sulfation; another metabolic pathway involves oxidation via CYP3A4.

Elimination.

The terminal half-life (T_1/2) is approximately 1 hour, and clearance is 0.1 L/h/kg. Several cases of delayed elimination have been observed. Due to the specific binding of pantoprazole to proton pumps in parietal cells, T_1/2 does not correlate with the much longer duration of action (acid secretion inhibition).

The majority of pantoprazole metabolites are excreted in urine (approximately 80%), with the remainder eliminated in feces. The main metabolite in both plasma and urine is desmethylpantoprazole sulfate conjugate. The T_1/2 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 (poor metabolizers). In these individuals, pantoprazole metabolism is likely primarily catalyzed by CYP3A4. After a single 40 mg dose, the mean AUC was approximately 6 times higher in poor metabolizers compared to individuals with functionally active CYP2C19 (extensive metabolizers). Mean C_max increased by approximately 60%. These findings do not affect pantoprazole dosing.

Patients with renal impairment.

Dose adjustment is not necessary in these patients (including those on dialysis). As in healthy volunteers, the T_1/2 of pantoprazole is short. Only a very small amount of pantoprazole is dialyzed. Although the main metabolite has a moderately prolonged T_1/2 (2–3 hours), elimination is rapid, so accumulation does not occur.

Patients with hepatic impairment.

Although in patients with liver cirrhosis (Child–Pugh classes A and B), T_1/2 increases to 7–9 hours and AUC increases 5–7 times, C_max increases only slightly—by 1.5 times compared to healthy volunteers.

Elderly patients.

A slight increase in AUC and C_max in elderly volunteers compared to younger volunteers is not clinically significant.

Children.

After a single oral dose of 20 mg or 40 mg of pantoprazole, AUC and C_max in children aged 5 to 16 years were within the range observed in adults. After a single intravenous dose of pantoprazole at 0.8 or 1.6 mg/kg in children aged 2 to 16 years, no significant relationship was observed between pantoprazole clearance and patient age or body weight. AUC and volume of distribution corresponded to those in adults.

Clinical characteristics.

Indications.

Adults and children aged 12 years and older.

• Gastroesophageal reflux disease (GERD) with 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 to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interactions.

Medicinal products whose bioavailability is pH-dependent (e.g., certain antifungal agents such as ketoconazole, itraconazole, posaconazole, or erlotinib)

Concomitant administration of pantoprazole may reduce the absorption of medicinal products whose bioavailability depends on gastric pH.

HIV protease inhibitors (atazanavir)

Concomitant use of proton pump inhibitors (PPIs) with atazanavir and other HIV protease inhibitors whose bioavailability is pH-dependent may lead to a significant reduction in their absorption and affect their efficacy (see section "Special warnings and precautions for use"). Concomitant administration of pantoprazole with HIV protease inhibitors (such as atazanavir) is not recommended. If concomitant use 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 the 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 abnormal bleeding and even death. Close monitoring of INR and prothrombin time is necessary when these agents are used concomitantly.

Methotrexate

It has been observed that concomitant administration of high-dose methotrexate (e.g., 300 mg) and PPIs may increase plasma methotrexate levels in some patients. Patients receiving high-dose methotrexate (e.g., those with cancer or psoriasis) should temporarily discontinue pantoprazole.

Medicinal products that inhibit or induce CYP2C19

Inhibitors of CYP2C19, such as fluvoxamine, may increase systemic exposure to pantoprazole. Consideration should be given to reducing the pantoprazole dose in patients on long-term, high-dose pantoprazole therapy and in 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.

Other interactions

Pantoprazole is predominantly 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 via these pathways—such as carbamazepine, diazepam, glyburide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—did not reveal clinically significant interactions. However, interactions with other agents metabolized via the same enzyme systems cannot be ruled out.

Results from multiple studies on potential interactions indicate that pantoprazole does not affect the metabolism of substances metabolized by CYP1A2 (e.g., caffeine, theophylline), CYP2C9 (e.g., piroxicam, diclofenac, naproxen), CYP2D6 (e.g., metoprolol), or CYP2E1 (e.g., ethanol). Pantoprazole does not affect P-glycoprotein, which is associated with digoxin absorption.

No interaction between pantoprazole and antacids has been observed.

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

Effect of the medicinal product on laboratory test results.

False-positive urine screening tests for tetrahydrocannabinol (THC) have been reported in patients receiving pantoprazole. Alternative testing methods should be considered to confirm test results.

Special precautions for use.

Long-term use

During prolonged use of the drug, especially for more than one year, patients should be under regular medical supervision.

Use in patients with impaired liver function

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

Use as part of combination therapy

When using the drug as part of combination therapy, the instructions for medical use of the corresponding medicinal products should be followed.

Risk of masking 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), or suspicion or presence of gastric ulcer, malignancy should be excluded. If symptoms persist despite adequate treatment, further investigation is required.

Concomitant use with 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 a significant reduction in their bioavailability (see section "Interaction with other medicinal products and other forms of interaction").

Effect on vitamin B12 absorption

In patients with Zollinger–Ellison syndrome and other hypersecretory conditions requiring long-term treatment, pantoprazole, like all drugs that inhibit hydrochloric acid production, may reduce absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in cases of weight loss, presence of risk factors for reduced vitamin B12 absorption during long-term use, or presence of relevant clinical symptoms.

Risk of gastrointestinal infections

Pantoprazole, like other PPIs, may increase the number of bacteria normally present in the upper gastrointestinal tract. Use of pantoprazole may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or C. difficile.

Risk of hypomagnesemia

Cases of severe hypomagnesemia have been reported in patients taking pantoprazole for at least 3 months, in most cases for one year or longer. Serious clinical manifestations of hypomagnesemia, which may develop initially unnoticed, 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), patients' condition improved in most cases after magnesium replacement therapy and discontinuation of pantoprazole.

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

Risk of bone fractures

Long-term (more than one year) use of high doses of the drug may slightly increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or in the presence of other risk factors. Observational studies indicate that pantoprazole use may increase the overall risk of fractures by 10–40%. Some of these may be attributable to other risk factors. Patients at risk of osteoporosis should receive treatment according to current clinical guidelines and should ensure adequate intake of vitamin D and calcium.

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions associated with pantoprazole use, which may be life-threatening or lead to fatal outcomes, including erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported during pantoprazole use. 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 indicating these reactions occur, pantoprazole should be discontinued immediately and alternative treatment considered.

Risk of subacute cutaneous lupus erythematosus

Pantoprazole use has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions develop, particularly 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 pantoprazole therapy may increase the risk of its occurrence with other PPIs.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels may interfere with diagnostic tests for neuroendocrine tumors. To avoid this interference, the drug 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 PPI therapy.

Excipients

The drug contains mannitol, which may have a mild laxative effect.

The drug contains sucrose; therefore, it should not be used in patients with rare hereditary problems of carbohydrate metabolism, such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome.

The drug contains less than 1 mmol sodium (23 mg)/1 tablet, i.e. practically 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 fetotoxic/neonatal toxicity. Reproductive toxicity was observed in animal studies. As a precautionary measure, pantoprazole use in pregnant women should be avoided.

Breastfeeding

Animal studies have shown excretion of pantoprazole into breast milk. Data on excretion of pantoprazole into 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 pantoprazole therapy should be made taking into account the benefit of breastfeeding for the child and the benefit of pantoprazole treatment for the woman.

Fertility

Pantoprazole did not impair fertility in animal studies.

Ability to influence reaction speed when driving or operating machinery

Pantoprazole has no effect or has a negligible effect on reaction speed when driving or operating machinery. However, the possible development of adverse reactions such as dizziness and visual disturbances should be taken into account (see section "Adverse reactions"). If such adverse reactions occur, patients should refrain from driving or operating machinery.

Dosage and Administration

The medication is intended for oral use. Tablets should be taken whole, without chewing or crushing, one hour before a meal, with water.

Adults and children aged 12 years and older

Gastroesophageal reflux disease (GERD)

The recommended dose is 40 mg (1 tablet) once daily. In individual cases, the dose may be doubled to 80 mg (2 tablets) daily, particularly if there is no response to other medications. Treatment of GERD usually requires 4 weeks. If healing is not achieved, further improvement may be expected during the subsequent 4 weeks.

Adults

H. pylori eradication 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 the selection and use of appropriate antibacterial agents should be considered. Depending on microbial sensitivity, the following therapeutic regimens may be prescribed for H. pylori eradication in adults:

a) 40 mg (1 tablet) pantoprazole twice daily

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

b) 40 mg (1 tablet) pantoprazole twice daily

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

c) 40 mg (1 tablet) pantoprazole 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 pantoprazole should be taken in the evening, one hour before a meal. The duration of treatment is 7 days and may be extended for another 7 days (total treatment duration not exceeding 2 weeks). If further treatment with pantoprazole is indicated to promote ulcer healing, refer to the recommended dosing for gastric and duodenal ulcers.

If combination therapy is not indicated, e.g., in patients with a negative H. pylori test, monotherapy with pantoprazole at the dosage specified below should be used.

Gastric ulcers

The recommended dose is 40 mg (1 tablet) once daily. In individual cases, the dose may be doubled to 80 mg (2 tablets) daily, particularly if there is no response to other medications. Treatment of gastric ulcers usually requires 4 weeks. If healing is not achieved, further improvement may be expected during the subsequent 4 weeks.

Duodenal ulcer

The recommended dose is 40 mg (1 tablet) once daily. In individual cases, the dose may be doubled to 80 mg (2 tablets) daily, particularly if there is no response to other medications. Treatment of duodenal ulcers usually requires 2 weeks. If healing is not achieved, further improvement may be expected during the subsequent 2 weeks.

Zollinger-Ellison syndrome and other hypersecretory conditions

For long-term treatment of Zollinger-Ellison syndrome and other pathological hypersecretory states, the recommended initial daily dose is 80 mg (2 tablets). If necessary, the dose may be subsequently adjusted (increased or decreased) depending on gastric acid secretion levels. If the daily dose exceeds 80 mg, it should be divided into two doses. Temporary dose increases above 160 mg of pantoprazole may be possible, but duration of use should be limited only to the period required for adequate control of acid secretion.

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

Patients with hepatic impairment

In patients with severe hepatic impairment, the daily dose of pantoprazole should not exceed 20 mg. Pantoprazole should not be used in patients with moderate to severe hepatic impairment for H. pylori eradication in combination therapy, as there are currently no data on the efficacy and safety of such use in this patient group.

Patients with renal impairment

Dosage adjustment is not necessary in these patients. Pantoprazole should not be used in patients with renal impairment for H. pylori eradication in combination therapy, as there are currently no data on the efficacy and safety of such use in this patient group.

Elderly patients

Dosage adjustment is not necessary in these patients.

Children

The medication may be used in children aged 12 years and older for the treatment of gastroesophageal reflux disease. The medication is not recommended for children under 12 years of age, as data on the safety and efficacy of pantoprazole in this age group are limited.

Overdose

Symptoms of overdose are unknown. Doses of pantoprazole up to 240 mg administered intravenously over 2 minutes have been well tolerated.

Since pantoprazole is highly protein-bound, it is not a substance that can be easily removed by dialysis.

In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy should be administered. There are no recommendations for specific antidotal treatment.

Adverse Reactions

Adverse reactions have been observed in approximately 5% of patients. The most commonly reported adverse reactions during pantoprazole treatment were diarrhea and headache (in approximately 1% of patients).

Adverse reactions are classified by frequency as follows: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000), very rare (< 1/10,000), and not known (frequency cannot be estimated from available data).

Within each frequency category, adverse reactions are listed in order of decreasing severity.

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), change in body weight; not known – hyponatremia, hypomagnesemia (see section "Special precautions"), hypocalcemia^1^, hypokalemia^1^.

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, as well as exacerbation of these symptoms if pre-existing).

Nervous system disorders:

Uncommon – headache, dizziness; rare – taste disturbances; not known – paresthesia.

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, gamma-glutamyltransferase); rare – increased bilirubin levels; not known – hepatocellular injury, jaundice, hepatocellular failure.

Skin and subcutaneous tissue disorders:

Uncommon – skin rash, 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 syndrome), erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special precautions").

Musculoskeletal and connective tissue disorders:

Uncommon – fractures of the femur, wrist, spine (see section "Special precautions"); rare – arthralgia, myalgia; not known – muscle spasms^2^.

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").

^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 highly important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions through the national reporting system.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in a dry, light-protected place, out of reach of children.

Packaging.

7 tablets per blister. 2 or 4 blisters per cardboard package.

Prescription status.

Prescription only.

Manufacturer.

UORLDMEDICINE ILAC SAN. VE TIC. A.S., Turkey / WORLD MEDICINE ILAC SAN. VE TIC. A.S., Turkey.

Manufacturer's address.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing authorization holder.

LLC "WORLD MEDICINE", Ukraine / WORLD MEDICINE, LLC, Ukraine.