INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PULCET® (PulCet®)

Composition:

Active substance: pantoprazole;

1 vial contains 40 mg of pantoprazole sodium sesquihydrate calculated as pantoprazole;

Excipients: disodium edetate, sodium hydroxide.

Pharmaceutical form. Lyophilized powder for solution for injection.

Main physicochemical characteristics: white to almost white powder.

Pharmacotherapeutic group.

Drugs for treatment of peptic ulcer and gastroesophageal reflux disease. ATC code A02BC02.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action. Pantoprazole is a substituted benzimidazole that inhibits gastric acid secretion by specifically blocking the proton pumps of parietal cells. Pantoprazole is transformed into its active form in the acidic environment of parietal cells, where it inhibits the H+-K+-ATPase enzyme, thus blocking the final step of gastric hydrochloric acid production. Inhibition is dose-dependent and affects 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-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 the same following oral or intravenous administration.

Pantoprazole use increases fasting gastrin levels. With short-term treatment, these levels usually do not exceed the upper limit of normal. With long-term treatment, gastrin levels typically double. Marked increases occur only in isolated cases. As a result, prolonged treatment may occasionally lead to mild or moderate increase in gastric enterochromaffin-like (ECL) cells (similar to adenomatoid hyperplasia). However, according to current studies, the development of neuroendocrine tumor precursors (atypical hyperplasia) or gastric neuroendocrine tumors, observed in animal studies, has not been observed 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 completely excluded.

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels rise. Elevated CgA levels may affect test results when diagnosing 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, which may be falsely elevated after PPI treatment, to return to the normal range.

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 approximately 0.15 L/kg.

Biological transformation. 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. 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 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%), with the remainder eliminated in feces. The main metabolite in both serum and urine is desmethylpantoprazole sulfate conjugate. The half-life of the main metabolite (approximately 1.5 hours) is only slightly longer than that of pantoprazole.

Special patient groups.

Poor metabolizers. Approximately 3% of Europeans have low functional activity of the CYP2C19 enzyme; they are referred to as poor metabolizers. In these individuals, pantoprazole metabolism is likely catalyzed primarily 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 peak plasma concentration increased by approximately 60%. These findings do not affect pantoprazole dosing.

Renal impairment. No dosage adjustment recommendations are required for pantoprazole in patients with impaired renal function (including dialysis patients). As in healthy volunteers, the half-life of pantoprazole remains short. Only very small amounts of pantoprazole are dialyzed. Although the main metabolite has a moderately prolonged half-life (2–3 hours), elimination remains rapid, so no accumulation occurs.

Hepatic impairment. Although in patients with liver cirrhosis (Child-Pugh classes A and B), the half-life of pantoprazole increases to 7–9 hours and AUC increases 5–7 times, the maximum serum concentration (Cmax) increases only slightly—by 1.5 times—compared to healthy volunteers.

Elderly patients. A slight increase in AUC and Cmax in elderly volunteers compared to younger volunteers is not clinically significant. Pediatric patients. After a single intravenous dose of pantoprazole at 0.8 or 1.6 mg/kg administered to 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 Pultset® is indicated for use in adults for:

gastroesophageal reflux disease (reflux esophagitis),
gastric and duodenal ulcers,
Zollinger-Ellison syndrome and other hypersecretory pathological conditions.

Contraindications.

Hypersensitivity to the active substance, benzimidazole derivatives, or to any component 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 (see section "Special precautions for use").

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 the development of pathological bleeding and even fatal outcomes. Monitoring of INR and prothrombin time is required when these medicinal products are used concomitantly.

Methotrexate. There have been reports that concomitant use of high-dose methotrexate (e.g., 300 mg) and PPIs increases methotrexate blood levels in some patients. Patients receiving high doses of methotrexate, such as those with cancer or psoriasis, should temporarily discontinue pantoprazole therapy.

Other interactions. Pantoprazole is predominantly metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19; 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—did not reveal clinically significant interactions.

Interaction between pantoprazole and other medicinal products metabolized via the same enzyme system 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), or CYP2E1 (e.g., ethanol), and does not affect P-glycoprotein associated with digoxin absorption.

No interaction was observed with concomitantly administered antacids.

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

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

Effect 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.

Malignant gastric 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 cases of suspected or confirmed gastric ulcer, the presence of a malignant process 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, pantoprazole therapy 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. Treatment with Pulcet® may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile.
Hypomagnesaemia. Rare cases of severe hypomagnesaemia have been reported in patients receiving 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 hypomagnesaemia may occur and initially develop insidiously: fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia. Hypomagnesaemia may lead to the development of hypocalcaemia and/or hypokalaemia (see section "Adverse reactions"). In cases of hypomagnesaemia (and hypocalcaemia and/or hypokalaemia associated with hypomagnesaemia), patients' condition improved in most cases after replacement therapy with magnesium supplements and discontinuation of PPI treatment.

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

Bone fractures. Long-term treatment (more than 1 year) with high doses of PPIs may moderately 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 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 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 have been reported during pantoprazole use (see section "Adverse reactions"), which may be fatal, such as 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. Patients should be informed about the signs and symptoms of severe skin reactions, and closely monitored for their development. If symptoms suggestive of these reactions occur, pantoprazole should be discontinued immediately and alternative treatment 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 Pulcet® should be considered. Development of subacute cutaneous lupus erythematosus during previous 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 tests for neuroendocrine tumors. To avoid such interference, treatment with Pulcet® should be temporarily discontinued at least 5 days before assessment of CgA levels (see section "Pharmacodynamics"). 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 therapy.

Important information on excipients.

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

Use during pregnancy or breastfeeding.

Pregnancy. Available data on the use of Pulcet® in pregnant women (approximately 300–1000 pregnancy outcome reports) indicate no embryonal or fetal/neonatal toxicity of pantoprazole. Reproductive toxicity was observed in animal studies. As a precautionary measure, the use of Pulcet® in pregnant women should be avoided.

Breastfeeding. Animal studies have shown excretion of pantoprazole into breast milk. There is insufficient data on excretion of pantoprazole into human breast milk, although such excretion has been reported. A risk to newborns/infants cannot be excluded. The decision whether to discontinue breastfeeding or to discontinue/abstain from Pulcet® therapy should be made taking into account the benefit of breastfeeding for the child and the benefit of Pulcet® therapy for the woman.

Fertility. Pantoprazole did not impair fertility in animal studies.

Ability to affect reaction speed when driving vehicles or operating machinery.

Pantoprazole has no effect or has a negligible effect on reaction speed when driving vehicles or operating machinery. However, the possible development of adverse reactions such as dizziness and visual disturbances should be considered (see section "Adverse reactions"). In such cases, driving vehicles or operating machinery should be avoided.

Method of Administration and Dosage

The medicinal product should be used as prescribed by a physician and under appropriate medical supervision.

Intravenous administration of the medicinal product is recommended only when oral administration is not possible. Data are available on intravenous treatment duration up to 7 days. Therefore, as soon as oral administration of pantoprazole becomes feasible, the transition from intravenous administration of PULCETâ to oral pantoprazole at a dose of 40 mg should be made.

Gastroesophageal reflux disease, duodenal ulcer, gastric ulcer.

The recommended dose is 40 mg of pantoprazole (1 vial) daily administered intravenously.

Treatment of Zollinger-Ellison syndrome and other hypersecretory conditions.

For long-term treatment of Zollinger-Ellison syndrome and other hypersecretory conditions, the recommended initial dose of PULCETâ 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. A temporary increase in pantoprazole dose above 160 mg may be possible, but the duration of use should be limited only to the period required for adequate control of acid secretion.

If rapid acid reduction is required, an initial dose of 2 × 80 mg is sufficient for most patients to achieve the desired level (< 10 mEq/h) within 1 hour.

Preparation for Use.

The powder should be dissolved in 10 mL of 0.9% sodium chloride solution provided in the vial. 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. After reconstitution, the chemical and physical stability of the medicinal product is maintained for 12 hours at 25 °C. From a microbiological standpoint, the diluted preparation should be used immediately.

PULCETâ 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. Any unused portion or product with altered physicochemical properties (e.g., color change, precipitation) must be disposed of according to local regulations. The reconstituted solution should be clear and yellowish.

Hepatic impairment. In patients with severe hepatic impairment, the daily dose should not exceed 20 mg (½ vial of PULCETâ, powder for solution for injection 40 mg) (see section "Special Warnings and Precautions for Use").

Renal impairment. Dose adjustment is not required in patients with renal impairment (see section "Pharmacokinetics").

Elderly patients. Dose adjustment is not required in elderly patients (see section "Pharmacokinetics").

Children.

PULCETâ, powder for solution for injection, is not recommended for use in children (under 18 years of age) due to limited data on safety and efficacy of pantoprazole in this age group. Current available data are described in the "Pharmacokinetics" section; however, dosage recommendations cannot be provided.

Overdose.

Symptoms. Symptoms of overdose are unknown.

Doses up to 240 mg administered intravenously over 2 minutes were well tolerated.

Treatment. Since pantoprazole is extensively protein-bound, it is not a drug that is readily dialyzable.

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

Adverse reactions

Adverse reactions may be expected to occur in approximately 5% of patients.

Adverse 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), frequency not known (frequency cannot be estimated from the available data).

For all adverse reactions reported during the post-marketing period, it is not possible to determine frequency; therefore, they are listed as "frequency not known". Within each frequency category, adverse reactions are listed in order of decreasing severity.

Blood and lymphatic system disorders

Rare: agranulocytosis.

Very rare: leukopenia, thrombocytopenia, pancytopenia.

Immune system disorders

Rare: hypersensitivity reactions (including anaphylactic reactions, anaphylactic shock).

Metabolism and nutritional disorders

Rare: hyperlipidemia and increased lipid levels (triglycerides, cholesterol), change in body weight.

Frequency 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).

Frequency not known: hallucination, confusion (particularly in patients predisposed to such disorders, and including 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, flatulence, 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 for use").

Musculoskeletal and connective tissue disorders

Uncommon: fractures of the femur, wrist, spine (see section "Special precautions for use").

Rare: arthralgia, myalgia.

Frequency not known: muscle spasms\textsuperscript{2}.

Renal and urinary disorders

Frequency not known: tubulointerstitial nephritis (with possible development of renal failure).

Reproductive system and breast disorders

Rare: gynecomastia.

General disorders

Common: thrombophlebitis 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 are encouraged to report any suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

After reconstitution, store for up to 12 hours at 25 °C.

Keep out of the reach and sight of children.

Packaging.

1 vial per carton.

Prescription status. Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address and place of business. Sankaklar Quarter, Eskiakcakoca Avenue, No. 299, 81100 Duzce, Turkey.