Ulsepan

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

Composition:

Active substance: pantoprazole;

1 vial contains pantoprazole (as pantoprazole sodium sesquihydrate) 40 mg;

Excipient: sodium hydroxide.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical characteristics: lyophilized powder white or almost white; solution: clear colorless or yellow solution.

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 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, thus blocking the final step of gastric hydrochloric acid production. 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 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 regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect of pantoprazole is equivalent 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 treatment, gastrin levels typically double in most cases. However, marked elevation occurs only in isolated cases. As a result, mild or moderate increase in the number of enterochromaffin-like (ECL) cells in the stomach may occasionally be observed during prolonged therapy (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, observed in animal studies, has not been reported in humans.

Based on animal study results, the influence 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 treatment.

Pharmacokinetics.

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

Distribution

Plasma protein binding of pantoprazole is approximately 98%. The volume of distribution is approximately 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; 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 action (acid secretion inhibition).

The majority of pantoprazole metabolites are excreted in urine (approximately 80%), the remainder in feces. The main metabolite in both plasma and urine is desmethylpantoprazole conjugated with sulfate. The half-life (T1/2) of the main metabolite (approximately 1.5 hours) slightly exceeds that of pantoprazole.

Special patient groups

Poor metabolizers

Approximately 3% of Europeans have low functional activity of the enzyme CYP2C19 and are referred to as poor metabolizers. In these individuals, pantoprazole metabolism is likely primarily catalyzed by the CYP3A4 enzyme. After a single 40 mg dose of pantoprazole, the mean area under the plasma concentration-time curve (AUC) was approximately 6 times higher in poor metabolizers than in individuals with functionally active CYP2C19 (extensive metabolizers). The mean maximum plasma concentration (Cmax) increased by approximately 60%. These findings do not affect pantoprazole dosing.

Patients with renal impairment

No dosage adjustment recommendations are required for pantoprazole in patients with impaired renal function (including patients on dialysis). As in healthy individuals, the T1/2 of pantoprazole is short. Only very small amounts of pantoprazole are dialyzed. Although the main metabolite has a moderately prolonged T1/2 (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), T1/2 increases to 7–9 hours and AUC increases 5–7 times, Cmax increases only slightly—by 1.5 times compared to healthy volunteers.

Elderly patients

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

Children

After single intravenous administration of pantoprazole at doses of 0.8 mg/kg or 1.6 mg/kg to children aged 2 to 16 years, no significant relationship 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.

The medicinal product is indicated for use in adults for:

• 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 depends on pH

Due to complete and prolonged inhibition of hydrochloric acid secretion, pantoprazole may affect the absorption of medicinal products for which gastric pH is an important factor of their bioavailability (e.g., certain antifungal agents such as ketoconazole, itraconazole, posaconazole, or other medicinal products 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 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 the international normalized ratio (INR). 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 pathological bleeding and even fatal outcomes. Monitoring of INR and prothrombin time is required when these agents are used concomitantly.

Methotrexate

There have been reports of increased plasma methotrexate levels in some patients when high-dose methotrexate (e.g., 300 mg) is administered concomitantly with PPIs. Patients receiving high-dose methotrexate, such as cancer or psoriasis patients, should temporarily discontinue pantoprazole treatment.

Medicinal products that inhibit or induce CYP2C19

CYP2C19 inhibitors, such as fluvoxamine, may increase the systemic exposure to pantoprazole. Consideration should be given to dose reduction 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.

Other interactions

Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19, followed by sulfate conjugation; another metabolic pathway involves 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—did not reveal clinically significant interactions. However, interactions between pantoprazole and other medicinal products metabolized via the same enzyme systems cannot be excluded.

Results from several 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), and does not affect P-glycoprotein associated with digoxin absorption.

No interaction has been observed with concomitantly administered antacids.

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

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 results.

Special precautions for use.

Malignant gastric neoplasms

Symptomatic response to pantoprazole may mask symptoms of malignant gastric tumors and delay their diagnosis. In the presence of alarm symptoms (e.g., significant weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena), as well as in suspected or confirmed gastric ulcer, malignancy must be excluded.

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, the drug should be discontinued (see section "Dosage and administration").

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").

Gastrointestinal infections caused by bacteria

Use of the drug 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), including pantoprazole, for at least three months, and in most cases after one year of treatment. Serious clinical manifestations of hypomagnesemia, which may 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 associated hypocalcemia and/or hypokalemia), patients' conditions generally improved after magnesium replacement therapy and discontinuation of PPI therapy.

Patients requiring long-term treatment, 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 therapy and periodically during treatment.

Bone fractures

Long-term (more than 1 year) high-dose PPI therapy may slightly 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 PPI use may increase the overall fracture risk by 10–40%. Some of these fractures may be attributable to other risk factors. Patients at risk of osteoporosis should receive treatment according to current clinical guidelines and ensure adequate intake of vitamin D and calcium.

Severe cutaneous adverse reactions

Severe, potentially life-threatening or fatal skin adverse reactions associated with pantoprazole use have been reported, 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 closely monitored. If symptoms suggestive of these reactions occur, pantoprazole should be discontinued immediately and alternative therapy considered.

Subacute cutaneous lupus erythematosus

PPI 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 during prior PPI therapy may increase the risk of recurrence with other PPIs.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels may interfere with diagnostic testing for neuroendocrine tumors. To avoid this interference, the drug should be temporarily discontinued at least 5 days before assessment of CgA levels. If CgA and gastrin levels do not return to normal after initial measurement, repeat testing should be performed 14 days after discontinuation of PPI therapy.

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

Use during pregnancy or breastfeeding.

Pregnancy

Available data on use in pregnant women (approximately 300–1000 reports on pregnancy outcomes) indicate no embryonal or fetotoxic/neonatal toxicity of pantoprazole. Reproductive toxicity was observed in animal studies. As a precautionary measure, use of the drug during pregnancy 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 whether to discontinue breastfeeding or to discontinue/abstain from drug therapy 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 affect reaction speed when driving or operating machinery.

Pantoprazole has no effect or a negligible effect on the ability to drive or operate machinery. However, the possible occurrence of adverse reactions such as dizziness and visual disturbances should be considered. 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 the direct supervision of a physician. 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 implemented.

Dosing

Gastroesophageal reflux disease, duodenal ulcer, gastric ulcer

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

Zollinger-Ellison syndrome and other hypersecretory conditions

The recommended initial dose of the medicinal product is 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 acid secretion control.

When rapid acid reduction is needed, 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

Patients with severe hepatic impairment should not exceed a daily dose of 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 dilution 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, the diluted solution should be used 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 administration, 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 data on safety and efficacy of pantoprazole in this age group are limited. Available information is described in the section "Pharmacokinetics"; however, dosing recommendations cannot be provided.

Overdose

Symptoms of overdose are unknown. Doses up to 240 mg administered intravenously over 2 minutes have been 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 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), frequency not known (frequency cannot be estimated from 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), change in body weight; frequency not known – hyponatremia, hypomagnesemia (see section "Special precautions"), hypocalcemia¹, hypokalemia¹.

Psychiatric disorders:

Uncommon – sleep disorders; rare – depression (including exacerbation); very rare – confusion (including exacerbation); frequency not known – hallucinations, confusion (especially 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; frequency 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; frequency not known – hepatocellular injury, jaundice, hepatocellular failure.

Skin and subcutaneous tissue disorders:

Uncommon – skin rash, exanthema, pruritus; rare – urticaria, angioneurotic edema; frequency 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").

Musculoskeletal and connective tissue disorders:

Uncommon – fractures of the femur, wrist, spine (see section "Special precautions"); rare – arthralgia, myalgia; frequency not known – muscle spasms².

Renal and urinary disorders:

Frequency 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.

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 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, pharmacists, patients, or 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 in the original packaging and in a place inaccessible to children.

Packaging.

1 vial in a blister pack, 1 blister pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLDMEDICINE ILAC SAN. VE TIC. A.S.
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of manufacturing site.

COSB G.O.Pasa Mah. 6. Cad. No:30, Cerkezkoy/Tekirdag, Turkey.