INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOLOPENT® (ZOLOPANT®)

Composition:

Active substance: pantoprazole;

1 tablet contains pantoprazole sodium sesquihydrate equivalent to pantoprazole 40 mg;

Excipients: sodium carbonate anhydrous, mannite (E 421), crospovidone, hydroxypropylcellulose, calcium stearate, methacrylic acid copolymer dispersion, triethyl citrate, sodium lauryl sulfate, titanium dioxide (E 171), yellow iron oxide (E 172), talc, Opadry 03F58750 white*.

* Opadry 03F58750 white: hypromellose, titanium dioxide (E 171), polyethylene glycol, talc.

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties: oval, biconvex, enteric-coated tablets of yellow color.

Pharmacotherapeutic group.

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

ATC code A02BC02.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Pantoprazole is a substituted benzimidazole that inhibits gastric 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 hydrochloric acid production in the stomach. 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. The increase in gastrin secretion is reversible. Since pantoprazole binds to the enzyme distal to the cellular receptor, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect after oral and intravenous administration of the drug is equivalent.

The use of pantoprazole increases fasting gastrin levels. With short-term use, these levels usually do not exceed the upper limit of normal. With long-term treatment, gastrin levels typically increase twofold. Marked elevation occurs only in isolated cases. As a consequence, mild or moderate increase in gastric enterochromaffin-like (ECL) cells (similar to adenomatoid hyperplasia) may occasionally be observed during prolonged treatment. However, according to available studies, the development of neuroendocrine tumor precursors (atypical hyperplasia) or gastric neuroendocrine tumors, observed in animal studies, has not been reported in humans.

Based on animal study results, a potential effect 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. In addition, due to decreased gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may interfere with diagnostic testing for neuroendocrine tumors. Available published data suggest 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.

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; plasma concentration remains stable with repeated dosing. 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. Absolute bioavailability of pantoprazole in 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. Food intake only increases the variability of the lag time.

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

Metabolism. The substance is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation via CYP2C19, followed by sulfate conjugation; 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 observed. 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 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 enzyme CYP2C19 and are referred to as 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). The mean peak plasma concentration increased by approximately 60%. These findings do not affect pantoprazole dosing.

Renal impairment. There are no recommendations for dose reduction when prescribing pantoprazole to patients with impaired renal function (including patients on dialysis). As in healthy volunteers, the elimination half-life of pantoprazole remains short. Only very small amounts of pantoprazole are dialyzed. Despite the moderately prolonged half-life of the main metabolite (2–3 hours), elimination remains rapid, and accumulation does not occur.

Hepatic impairment. Although in patients with liver cirrhosis (Child-Pugh classes A and B), the half-life 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 or 40 mg pantoprazole, AUC and C_max in children aged 5 to 16 years were within the range of corresponding values in adults. After a single intravenous administration of pantoprazole at doses of 0.8 or 1.6 mg/kg to children aged 2 to 16 years, no significant relationship between pantoprazole clearance and patient age or body weight was observed. AUC and volume of distribution were comparable to those in adults.

Clinical characteristics.

Indications.

Adults and children aged 12 years and older.

Gastroesophageal reflux disease (GERD) with reflux 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 or to any component of the medicinal product, or to benzimidazole derivatives.

Interaction with other medicinal products and other forms of interaction.

Medicinal products whose absorption is pH-dependent. Due to the complete and long-lasting inhibition of gastric acid secretion, pantoprazole may affect the absorption of drugs for which gastric pH is an important factor in their bioavailability (e.g., certain antifungal agents such as ketoconazole, itraconazole, posaconazole, or other drugs such as erlotinib).

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

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 PPIs concomitantly with warfarin or phenprocoumon. Elevated INR and prolonged prothrombin time may lead to pathological bleeding and even fatal outcomes. Monitoring of INR and prothrombin time is required when these drugs are used concomitantly.

Methotrexate. Elevated blood levels of methotrexate have been observed in some patients when high-dose methotrexate (e.g., 300 mg) is administered concomitantly with PPIs. Patients receiving high-dose 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, with additional metabolic pathways including oxidation by CYP3A4. Studies with drugs that are also metabolized via these pathways (carbamazepine, diazepam, glibenclamide, nifedipine, phenytoin, oral contraceptives containing levonorgestrel and ethinylestradiol) have not revealed clinically significant interactions.

Interactions between pantoprazole and other drugs metabolized by this 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 involved in digoxin absorption.

No interaction has been observed with concomitantly administered antacids.

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

Drugs 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 by these enzyme systems.

Effect of medicinal products on laboratory test results. False-positive results in certain urine drug screening tests for tetrahydrocannabinol (THC) have been reported in patients taking pantoprazole. Alternative confirmatory testing methods should be considered to verify positive results.

Special precautions for use.

Hepatic impairment. Patients with severe impairment of liver function should have regular monitoring of liver enzymes, especially during long-term treatment. If liver enzyme levels increase, treatment with the medicinal product must be discontinued (see section "Dosage and administration").

Combination therapy. During combination therapy, the instructions for medical use of the respective medicinal products must be followed.

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, anaemia, 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.

HIV protease inhibitors. Concomitant use of pantoprazole with HIV protease inhibitors (e.g., 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").

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

Long-term treatment. Patients undergoing long-term treatment, particularly longer than one year, should be under regular medical supervision.

Gastrointestinal infections caused by bacteria. Treatment with pantoprazole may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile.

Hypomagnesaemia. Cases of severe hypomagnesaemia have been observed in patients treated with PPIs such as pantoprazole for at least three months, and in most cases after one year. Serious clinical manifestations of hypomagnesaemia, which may initially be asymptomatic, include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia. Hypomagnesaemia may lead to the development of hypocalcaemia and/or hypokalaemia (see section "Undesirable effects"). In cases of hypomagnesaemia (and hypocalcaemia and/or hypokalaemia associated with hypomagnesaemia), patients' conditions improved in most cases after corrective replacement therapy with magnesium and discontinuation of PPI treatment.

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

Bone fractures. Long-term (more than one year) high-dose PPI treatment may moderately increase the risk of hip, wrist, and spine fractures, particularly in elderly patients or those with other risk factors. Observational studies suggest that PPI 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 developing osteoporosis should receive treatment according to current clinical guidelines and consume adequate amounts of vitamin D and calcium.

Severe cutaneous adverse reactions. Serious cutaneous adverse reactions associated with pantoprazole use, with unknown frequency (see section "Undesirable effects"), potentially life-threatening or fatal, such as erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported. Patients should be informed about the signs and symptoms of these skin reactions and closely monitored for their development. If signs or symptoms suggestive of these reactions occur, pantoprazole should be discontinued immediately and alternative treatment considered.

Subacute cutaneous lupus erythematosus. PPI use has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions develop, especially in sun-exposed areas, accompanied by arthralgia, the patient should seek immediate medical attention, and discontinuation of pantoprazole should be considered. Development of subacute cutaneous lupus erythematosus in patients during previous PPI therapy may increase the risk of its recurrence with other PPIs.

Effect on laboratory test results.

Elevated chromogranin A (CgA) levels may interfere with diagnostic tests for neuroendocrine tumours. To avoid this interference, pantoprazole treatment 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 treatment.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially 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 foeto-neonatal toxicity of the drug. 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. 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 pantoprazole treatment should be made taking into account the benefits of breastfeeding for the child and the benefits of pantoprazole treatment 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 reaction speed when driving or operating machinery. The possible occurrence of adverse reactions such as dizziness and visual disturbances should be considered (see section "Undesirable effects"). In such cases, driving or operating machinery should be avoided.

Method of Administration and Dosage

Zolopent®, enteric-coated tablets, should be taken whole, 1 hour before a meal. Do not chew or crush the tablets. Swallow with water.

Recommended Dosage

Adults and Children Aged 12 Years and Older

Treatment of Reflux Esophagitis

The recommended dose is 1 tablet of Zolopent® 40 mg once daily. In some cases, the dose may be doubled (2 tablets of Zolopent® 40 mg per day), especially if there is no response to other treatments for reflux esophagitis.

Treatment of reflux esophagitis usually lasts 4 weeks. If this is insufficient, healing may be expected during the following 4 weeks.

Adults

Eradiation of H. pylori in Combination with Two Antibiotics

In adult patients with gastric or duodenal ulcer and a positive test for H. pylori, 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 susceptibility, the following therapeutic regimens may be prescribed for H. pylori eradication in adults:

a) 1 tablet of Zolopent® 40 mg twice daily + 1000 mg amoxicillin twice daily + 500 mg clarithromycin twice daily;

b) 1 tablet of Zolopent® 40 mg twice daily + 400–500 mg metronidazole (or 500 mg tinidazole) twice daily + 250–500 mg clarithromycin twice daily;

c) 1 tablet of Zolopent® 40 mg 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 Zolopent® 40 mg should be taken in the evening, 1 hour before a meal. The duration of treatment is 7 days and may be extended for another 7 days, with a total treatment duration not exceeding 2 weeks. If further treatment with pantoprazole is indicated to ensure ulcer healing, dosage recommendations for gastric and duodenal ulcers should be considered.

If combination therapy is not indicated, e.g., in patients with a negative H. pylori test, monotherapy with Zolopent® 40 mg should be administered at the dosage specified below.

Treatment of Gastric Ulcer

1 tablet of Zolopent® 40 mg once daily. In some cases, the dose may be doubled (2 tablets of Zolopent® 40 mg per day), especially if there is no response to other treatments.

Treatment of gastric ulcer usually lasts 4 weeks. If this is insufficient, ulcer healing may be expected during the following 4 weeks.

Treatment of Duodenal Ulcer

1 tablet of Zolopent® 40 mg once daily. In some cases, the dose may be doubled (2 tablets of Zolopent® 40 mg per day), especially if there is no response to other treatments.

Treatment of duodenal ulcer usually lasts 2 weeks. If this is insufficient, ulcer healing may be expected during the following 2 weeks.

Treatment of Zollinger–Ellison Syndrome and Other Hypersecretory Conditions

For long-term treatment of Zollinger–Ellison syndrome and other pathological hypersecretory conditions, the initial daily dose is 80 mg (2 tablets of Zolopent® 40 mg). If necessary, the dose may be subsequently titrated up or down depending on gastric acid secretion parameters. Doses exceeding 80 mg per day should be divided into two doses. A temporary increase in dose above 160 mg of pantoprazole may be possible, but the duration of such treatment should be limited to the period required for adequate acid control.

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 should not exceed 20 mg (1 tablet of Zolopent® 20 mg). Zolopent® should not be used for H. pylori eradication in combination therapy in patients with moderate to severe hepatic impairment, 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 required in patients with renal impairment. Zolopent® should not be used for H. pylori eradication in combination therapy in patients with renal impairment, as there are currently no data on the efficacy and safety of use in this patient group.

Elderly Patients
Elderly patients do not require dosage adjustment.

Children
Zolopent® 40 mg is indicated for children aged 12 years and older for the treatment of reflux esophagitis. The drug 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 up to 240 mg administered intravenously over 2 minutes have been well tolerated. Since pantoprazole is highly protein-bound, it is not a drug 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 were observed in approximately 5% of patients.

Undesirable effects 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 (≥ 1/10000 and < 1/1000), very rare (< 1/10000), and not known (frequency cannot be determined from available data).

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

Blood and lymphatic system disorders: rare: agranulocytosis; very rare: leukopenia, thrombocytopenia, pancytopenia.

Immune system disorders: rare: hypersensitivity reactions (including anaphylactic reactions, anaphylactic shock).

Metabolism and nutrition disorders: rare: hyperlipidemia and increased lipid levels (triglycerides, cholesterol); change in body weight; not known: hyponatremia, hypomagnesemia (see section "Special precautions for use"), hypocalcemia¹, hypokalemia¹.

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: 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; 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, toxic epidermal necrolysis (Lyell's syndrome), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special precautions for use").

Musculoskeletal and connective tissue disorders: uncommon: fractures of the hip, wrist, or spine (see section "Special precautions for use"); rare: arthralgia, myalgia; not known: muscle spasms².

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 for use").

² Muscle spasms as a result of electrolyte imbalance.

Reporting suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization 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, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

14 tablets in a blister; 1 blister per cardboard pack.

10 tablets in a blister; 3 blisters per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

KUSUM PHARM LTD.

Manufacturer's address and location of operations.

54 Skryabina Street, Sumy, Sumy region, 40020, Ukraine.

Manufacturer.

GLEDFARM LTD.

Manufacturer's address and location of operations.

54 Davydovskoho Hryhorii Street, Sumy, Sumy region, 40020, Ukraine.