Ulsepan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ULSEPAN (ULSEPAN)

Composition:

Active substance: pantoprazole;

1 vial contains pantoprazole (in the form of pantoprazole sodium sesquihydrate) 40 mg;

Excipient: sodium hydroxide.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical characteristics: lyophilized powder white or almost white; reconstituted solution: clear, colorless or slightly yellowish.

Pharmacotherapeutic group.

Drugs for the 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 the proton pumps of parietal cells. Pantoprazole is transformed into its active form in the acidic environment of parietal cells, where it inhibits the enzyme H⁺-K⁺-ATPase, thereby blocking the final step of hydrochloric acid production in the stomach. The inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. 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 reduction in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds to 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 or intravenous administration.

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

Based on animal study results, an effect of long-term (more than one year) 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 decreased gastric acidity, chromogranin A (CgA) levels rise. Elevated CgA levels may affect test results in the diagnosis of 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 the normal range, which may otherwise be falsely elevated after PPI therapy.

Pharmacokinetics

Pharmacokinetic properties do not change after single or repeated administration. Within the dose range of 10 to 80 mg, the pharmacokinetics of pantoprazole in plasma remain linear, both after oral administration and intravenous infusion.

Distribution

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

Biological Transformation

Pantoprazole is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation via CYP2C19, followed by sulfation; another metabolic pathway involves 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 reported. Due to the specific binding of pantoprazole to proton pumps in parietal cells, the elimination half-life does not correlate with the much longer duration of action (acid secretion inhibition).

The majority of pantoprazole metabolites are excreted in urine (about 80%), the remainder in feces. The main metabolite in both plasma and urine is desmethylpantoprazole conjugated with sulfate. The half-life (T_1/2) of the main metabolite (about 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 enzyme CYP2C19; they are referred to as poor metabolizers. In these individuals, pantoprazole metabolism is likely primarily catalyzed by the enzyme CYP3A4. After a single 40 mg dose of pantoprazole, the mean area under the plasma concentration-time curve (AUC) was approximately 6 times higher in poor metabolizers than in individuals with functionally active CYP2C19 (extensive metabolizers). The mean peak plasma concentration (C_max) increased by approximately 60%. These findings do not affect pantoprazole dosing.

Patients with Renal Impairment

No dose adjustment recommendations are required for pantoprazole in patients with impaired renal function (including patients on dialysis). As in healthy individuals, the T_1/2 of pantoprazole is short. Only very small amounts of pantoprazole are dialyzed. Despite the moderately prolonged T_1/2 of the main metabolite (2–3 hours), elimination remains rapid, and therefore no accumulation occurs.

Patients with Hepatic Impairment

Although in patients with liver cirrhosis (Child-Pugh classes A and B), the 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

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

Pediatric Patients

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 were consistent with data obtained from adult studies.

Clinical characteristics.

Indications.

The medicinal product is indicated for use in adults for:

• gastroesophageal reflux disease (reflux esophagitis);
• duodenal ulcer;
• gastric ulcer;
• Zollinger-Ellison syndrome and other hypersecretory conditions.

Contraindications.

Hypersensitivity to pantoprazole, benzimidazole derivatives, and/or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interactions.

Medicinal products 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 of their bioavailability (e.g., certain antifungal agents such as ketoconazole, itraconazole, posaconazole, or other agents 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.

If 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 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 concomitant PPIs and warfarin or phenprocoumon. Increased INR and prolonged prothrombin time may lead to the development of pathological bleeding and even fatal outcomes. Monitoring of INR and prothrombin time is necessary in such cases of concomitant use.

Methotrexate.

There have been reports that concomitant administration of high doses of methotrexate (e.g., 300 mg) and PPIs increases methotrexate plasma levels in some patients. Patients receiving high doses of methotrexate, such as those with cancer or psoriasis, should be advised to temporarily discontinue pantoprazole treatment.

Medicinal products that inhibit or induce CYP2C19.

Inhibitors of CYP2C19, such as fluvoxamine, may increase the systemic effect of pantoprazole. Consideration should be given to dose reduction in patients receiving 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 followed by sulfate conjugation; other metabolic pathways include oxidation by CYP3A4. 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. Interaction between pantoprazole and other drugs metabolized via the same enzyme system cannot be excluded.

Results from a number of 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), CYP2E1 (e.g., ethanol), nor does it affect

P-glycoprotein associated with digoxin absorption.

No interaction has been observed with concomitantly administered antacids.

Studies have been conducted to investigate the interaction of pantoprazole with concomitantly administered certain antibiotics (clarithromycin, metronidazole, amoxicillin). No clinically significant interactions were observed between these agents.

Effect of the medicinal product 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 test results.

Special precautions for use.

Gastric malignant neoplasms.

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

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

Hepatic impairment.

Patients with severe hepatic impairment require regular monitoring of liver enzymes. If liver enzymes increase, treatment with the medicinal product should be discontinued (see section "Dosage and 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 a significant reduction in their bioavailability (see section "Interaction with other medicinal products and other forms of interactions").

Gastrointestinal infections caused by bacteria.

Use of the medicinal product may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile.

Hypomagnesemia.

Rare cases of severe hypomagnesemia have been observed in patients treated with proton pump inhibitors (PPIs), such as pantoprazole, for at least three months, and in most cases, after one year of treatment. Serious clinical manifestations of hypomagnesemia, which may initially develop insidiously, include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. Hypomagnesemia may lead to the development of hypocalcemia and/or hypokalemia (see section "Undesirable effects"). In cases of hypomagnesemia (and hypocalcemia and/or hypokalemia associated with hypomagnesemia), patients' conditions improved in most cases after magnesium replacement therapy and discontinuation of PPI treatment.

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

Bone fractures.

Long-term treatment (more than 1 year) with high doses of PPIs may slightly increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other risk factors.

Observational studies indicate that the use of proton pump inhibitors may increase the overall risk of fractures by 10–40%. Some of these may be attributable 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 cutaneous adverse reactions.

Severe cutaneous adverse reactions associated with the use of pantoprazole, which may be life-threatening or fatal, have been reported during pantoprazole use, including erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). The frequency of these reactions is unknown (see section "Undesirable effects"). Patients should be informed about the signs and symptoms and monitored closely. If symptoms indicating these reactions occur, pantoprazole should be discontinued immediately, and alternative treatment options should be considered.

Subacute cutaneous lupus erythematosus.

The use of PPIs 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 medicinal product should be considered. Development of subacute cutaneous lupus erythematosus in patients during previous PPI therapy may increase the risk of its recurrence when using other PPIs.

Effect on laboratory test results.

Elevated chromogranin A (CgA) levels may interfere with diagnostic tests for neuroendocrine tumors. To avoid such interference, treatment with the medicinal product should be temporarily discontinued at least 5 days before assessing CgA levels. If CgA and gastrin levels have not returned to normal range after initial measurement, repeat measurements should be performed 14 days after discontinuation of PPI treatment.

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

Use during pregnancy or breastfeeding.

Pregnancy.

Available data on use in pregnant women (approximately 300–1000 pregnancy outcomes reported) indicate no embryonal or fetotoxic/neonatal toxicity of pantoprazole. Reproductive toxicity was observed in animal studies. As a precautionary measure, use of the medicinal product during pregnancy should be avoided.

Breastfeeding period.

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 use of the medicinal product should be made taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility.

Pantoprazole did not impair fertility in animal studies.

Ability to influence reaction rate when driving or operating machinery.

Pantoprazole has no effect or a negligible effect on reaction speed when driving or operating machinery. Possible development of adverse reactions such as dizziness and visual disturbances should be taken into account. If such reactions occur, driving or operating machinery should be avoided.

Dosage and Administration

The medicinal product should be used in adults as prescribed and under direct medical supervision. Intravenous administration of the medicinal product is recommended only when oral administration is not feasible. Safety data available refer to intravenous use for up to 7 days. Therefore, whenever clinically possible, transition from intravenous pantoprazole to oral pantoprazole at a dose of 40 mg should be performed.

Dosing.

Reflux esophagitis, duodenal ulcer, gastric ulcer.

The medicinal product should be administered at a dose of 40 mg (1 vial) daily intravenously.

Zollinger-Ellison syndrome and other hypersecretory conditions.

The medicinal product should be administered at the recommended initial dose of 80 mg daily. If necessary, the dose may be titrated up or down depending on gastric acid secretion parameters. Doses exceeding 80 mg daily should be divided into two administrations. Temporary dose increases above 160 mg may be considered, but duration of use should be limited only to the period required for adequate control of acid secretion.

In cases where rapid acid reduction is required, an initial dose of 80 mg twice is sufficient for most patients to achieve the desired level (< 10 mEq/h) within 1 hour.

Hepatic impairment.

In patients with severe hepatic impairment, the daily dose should not exceed 20 mg (½ vial).

Renal impairment.

Patients with impaired renal function do not require dose adjustment.

Elderly patients.

No dose adjustment is necessary.

Administration method.

Dissolve the powder in 10 mL of 0.9% sodium chloride solution. The solution may be administered directly or after mixing with 100 mL of 0.9% sodium chloride solution or 5% glucose solution in plastic or glass infusion bottles.

The prepared solution is stable for 12 hours at temperatures not exceeding 25 °C.

However, in order to maintain microbiological integrity, it is recommended to use the diluted solution immediately.

The medicinal product must not be prepared or mixed with solvents other than those specified above.

Intravenous administration of the medicinal product should be performed over 2–15 minutes.

The vial is intended for single use only. Before use, vials should be visually inspected (particularly for color changes or presence of precipitate).

The diluted solution should be colorless or slightly yellow.

Children.

The medicinal product is not recommended for use in children (under 18 years of age), as safety and efficacy data for pantoprazole in this age group are limited. Currently available information is described in the "Pharmacokinetics" section; however, dosing 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 highly protein-bound, it is not readily dialyzable.

In cases of overdose with clinical signs of intoxication, symptomatic and supportive therapy should be administered. There are no specific antidotes or recommended specific treatments.

Side effects

Side effects are classified by frequency of occurrence into the following categories: 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 the available data).

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"), hypocalcemia\textsuperscript{1}, hypokalemia\textsuperscript{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 previously present).

Nervous system disorders:

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

Eye disorders:

Rare – visual disturbances/blurred vision.

Gastrointestinal disorders:

Common – fundic gland polyps (benign); uncommon – diarrhea, nausea, vomiting, abdominal distension, constipation, dry mouth, abdominal pain and discomfort; not known – microscopic colitis.

Hepatobiliary disorders:

Uncommon – increased liver enzymes (transaminases, γ-GT); rare – increased bilirubin levels; not known – hepatocellular injury, jaundice, hepatocellular failure.

Skin and subcutaneous tissue disorders:

Uncommon – skin rashes, exanthema, pruritus; rare – urticaria, angioneurotic edema; not known – Stevens-Johnson syndrome, Lyell’s syndrome (toxic epidermal necrolysis), erythema multiforme, photosensitivity, drug reaction with eosinophilia and systemic symptoms (DRESS), 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 spasms\textsuperscript{2}.

Renal and urinary disorders:

Not known – tubulointerstitial nephritis (with possible development of renal failure).

Reproductive system and breast disorders:

Rare – gynecomastia.

General disorders and administration site conditions:

Common – phlebitis at the injection site; uncommon – asthenia, fatigue, malaise; rare – increased body temperature, peripheral edema.

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

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after a medicinal product is authorized 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, are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C, protected from light and out of reach of children.

Packaging.

1 vial with lyophilisate for solution for injection in a blister pack, 1 blister pack per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Mefar Ilac San. A.S., Turkey.

Manufacturer's address and location of business activity.

Ramazanoglu Mah. Ensar Cad. No: 20, 34906 Kurtkoy - Pendik/Istanbul, Turkey.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine.