Zolopent®
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZOLOPENT® (ZOLOPANT®)
Composition:
Active substance: pantoprazole;
One tablet contains pantoprazole sodium sesquihydrate equivalent to 20 mg of pantoprazole;
Excipients: anhydrous sodium carbonate, 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, yellow in color.
Pharmacotherapeutic group.
Drugs for the treatment of acid-related disorders. Proton pump inhibitor.
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, thereby blocking the final step of gastric acid production. Inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. Most patients are relieved of symptoms within 2 weeks. The use of pantoprazole, as well as other proton pump inhibitors (PPIs) and H2-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 gastric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same following oral or intravenous administration.
With pantoprazole use, fasting gastrin levels increase. During short-term treatment, gastrin levels in most cases do not exceed the upper limit of normal. During long-term treatment, gastrin levels typically double. However, excessive increases occur only in isolated cases. As a result, mild or moderate increase in specific endocrine (ECL) cells in the stomach (similar to adenomatoid hyperplasia) may occasionally be observed during prolonged therapy. However, according to studies conducted to date, the formation of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors, which were observed in animal studies, has not been observed in humans. Based on animal studies, the influence of long-term (more than one year) pantoprazole treatment on endocrine parameters of the thyroid gland 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 increase. Elevated CgA levels may interfere with diagnostic testing for 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, as they may be falsely elevated after PPI treatment.
Pharmacokinetics.
Absorption.
Pantoprazole is rapidly absorbed, and maximum plasma concentration is achieved after a single oral dose of 20 mg. On average, peak serum concentration (Cmax) of about 1–1.5 µg/mL is reached within 2–2.5 hours after administration; plasma concentration remains consistent after repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. In the dose range of 10 to 80 mg, the plasma pharmacokinetics of pantoprazole remain linear both after oral administration and intravenous infusion. Absolute bioavailability of tablets is approximately 77%. Concomitant food intake does not affect the area under the plasma concentration–time curve (AUC) or Cmax, and thus does not affect bioavailability. However, food intake only increases the variability of the latency period.
Distribution.
Plasma protein binding of pantoprazole is about 98%. The volume of distribution is approximately 0.15 L/kg.
Metabolism. Pantoprazole 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 about 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 reflect 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 serum and urine is desmethylpantoprazole sulfate conjugate. The half-life of the main metabolite (about 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; these individuals are referred to as poor metabolizers. In such individuals, pantoprazole metabolism is likely primarily catalyzed by the CYP3A4 enzyme. After a single 40 mg dose of pantoprazole, AUC was approximately 6 times higher in poor metabolizers than in individuals with functionally active CYP2C19 (extensive metabolizers). The average peak plasma concentration increased by approximately 60%. These findings do not affect pantoprazole dosing.
Renal impairment. No dosage adjustment recommendations are required 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, so accumulation does not occur.
Hepatic impairment. Although in patients with liver cirrhosis (Child-Pugh classes A and B) the elimination half-life increases to 3–6 hours and AUC increases by 3–5 times, Cmax increases only slightly—by 1.3 times compared to healthy volunteers.
Elderly patients. The slight increase in AUC and Cmax observed 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 Cmax in children aged 5 to 16 years were within the range of values observed in adults.
After a single intravenous dose of pantoprazole at 0.8 or 1.6 mg/kg in children aged 2 to 16 years, no significant relationship was observed between pantoprazole clearance and patient age or body weight. AUC and volume of distribution corresponded to data obtained in adult studies.
Clinical characteristics.
Indications.
Adults and children aged 12 years and older.
Symptomatic treatment of gastroesophageal reflux disease.
Long-term treatment and prevention of recurrence of reflux esophagitis.
Adults.
Prevention of gastric and duodenal ulcer associated with the use of non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk who require long-term NSAID therapy.
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 complete and prolonged inhibition of hydrochloric acid secretion, pantoprazole may affect the absorption of drugs for which gastric juice pH is an important factor for 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 dependent on intragastric pH, is not recommended due to significant reduction in their bioavailability (see section "Special warnings and 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 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 development of pathological bleeding and even fatal outcomes. Monitoring of INR and prothrombin time is necessary when these drugs are used concomitantly.
Metotrexate. It has been observed that concomitant administration of high doses of 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 extensively 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, glyburide, nifedipine, phenytoin, oral contraceptives containing levonorgestrel and ethinylestradiol) did not reveal clinically significant interactions.
Interaction between pantoprazole and other drugs metabolized by the same enzyme system cannot be excluded.
Results from multiple 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 potential interactions between pantoprazole and certain concomitantly administered antibiotics (clarithromycin, metronidazole, amoxicillin) have been conducted. No clinically significant interactions were observed between these drugs.
Medicinal products that inhibit or induce CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, may increase systemic exposure to pantoprazole. Consideration should be given to reducing the 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 of medicinal products on laboratory test results. False-positive results in certain urine screening tests for tetrahydrocannabinol have been reported in patients taking pantoprazole. Alternative confirmatory testing methods should be considered to confirm positive results.
Special precautions for use.
Hepatic impairment. Patients with severe liver dysfunction should have regular monitoring of liver enzymes, especially during prolonged treatment. If liver enzyme levels increase, treatment with the medicinal product should be discontinued (see section "Dosage and administration").
Concomitant use with NSAIDs. The use of Zolopent® 20 mg tablets for prevention of gastric and duodenal ulcers associated with long-term NSAID therapy should be restricted to patients who are prone to frequent ulcer relapses.
Risk assessment should take into account individual risk factors, including age (>65 years), history of gastric or duodenal ulcer, and gastrointestinal bleeding.
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), or suspicion or presence of gastric ulcer, malignancy must be excluded. If symptoms persist despite adequate treatment, further investigation is required.
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").
Vitamin B12 absorption. Pantoprazole may reduce absorption of vitamin B12 (cyanocobalamin) due to the development of hypo- or achlorhydria. This should be considered in patients with low body weight, risk factors for reduced vitamin B12 absorption during long-term treatment, or presence of relevant clinical symptoms.
Long-term therapy. 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.
Hypomagnesemia. Cases of severe hypomagnesemia have been observed in patients treated with proton pump inhibitors (PPIs), such as pantoprazole, for at least three months, and mostly after a year of treatment. Serious clinical manifestations of hypomagnesemia, such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia, may occur and initially develop insidiously. 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), the condition of most patients improved after magnesium replacement therapy and discontinuation of PPIs.
Patients requiring long-term therapy, or those taking PPIs concomitantly with digoxin or medications that may cause hypomagnesemia (e.g., diuretics), should have serum magnesium levels assessed before starting PPI treatment and periodically during therapy.
Bone fractures. Long-term (more than one year) and high-dose PPI therapy may moderately increase the risk of fractures of the hip, wrist, and spine, particularly in elderly patients or those with other risk factors. PPI use is known to 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. 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 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 pantoprazole 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 this interference, pantoprazole treatment should be temporarily discontinued at least 5 days before CgA assessment (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.
This 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 the use of pantoprazole in pregnant women (approximately 300–1000 pregnancy outcomes reported) indicate no embryonal or fetoneonatal toxicity of the drug. Reproductive toxicity was observed in animal studies. As a precautionary measure, pantoprazole should be avoided during pregnancy.
Breastfeeding. Animal studies have shown excretion of pantoprazole into breast milk. Data on excretion of pantoprazole into human breast milk are limited, but such excretion has been reported. Risk to newborns/infants cannot be excluded. The decision to discontinue breastfeeding or to discontinue/abstain from pantoprazole therapy should be made taking into account the benefit of breastfeeding for the child and the benefit of pantoprazole therapy for the woman.
Fertility. Pantoprazole did not impair fertility in animal studies.
Ability to influence reaction speed when driving or operating machinery. Pantoprazole has no effect or a negligible effect on reaction speed when driving or operating machinery. However, 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.
Administration and Dosage
Zolopent®, 20 mg tablets, should be taken whole, one hour before a meal. Do not chew or crush the tablets. Swallow with water.
Recommended dosage
Adults and children aged 12 years and older
Symptomatic treatment of gastroesophageal reflux disease (GERD).
The recommended dose is 20 mg (1 tablet) of Zolopent® once daily. Heartburn symptoms usually resolve within 2–4 weeks. If this period is insufficient, treatment may be continued for an additional 4 weeks. After symptom resolution, symptom recurrence can be managed on-demand by taking 20 mg of the drug once daily, i.e., 1 tablet as needed. A switch to long-term therapy should be considered if adequate symptom control is not achieved with on-demand treatment.
Long-term treatment and prevention of reflux esophagitis relapses.
For long-term maintenance therapy, the recommended dose is 20 mg (1 tablet) of Zolopent® once daily. During disease exacerbations, the dose may be increased to 40 mg daily. In such cases, Zolopent® 40 mg tablets are recommended. After resolution of the relapse, the dose may be reduced again to 20 mg once daily.
Adults
Prevention of gastric and duodenal ulcers associated with long-term use of non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) in patients at risk who require prolonged NSAID therapy.
The recommended dose is 20 mg (1 tablet) of Zolopent® once daily.
Hepatic impairment. In patients with severe liver dysfunction, the dose should not exceed 20 mg (1 tablet) per day.
Renal impairment. Dose adjustment is not required in patients with renal impairment.
Elderly patients do not require dose adjustment.
Children. The drug is not recommended for children under 12 years of age, as data on safety and efficacy in this age group are limited.
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 case of overdose with clinical signs of intoxication, symptomatic and supportive treatment should be administered. There are no specific antidotes or recommended specific therapies.
Side effects.
The occurrence of adverse reactions was 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 (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), and not known (frequency cannot be estimated from available data).
Within each frequency category, adverse reactions are listed in order of decreasing severity.
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"), 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: paresthesia.
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, Lyell's syndrome (toxic epidermal necrolysis), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special precautions").
Musculoskeletal and connective tissue disorders: uncommon: fractures of the femur, wrist, or spine (see section "Special precautions"); 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").
2 Muscle spasms as a result of electrolyte imbalance.
Reporting suspected adverse reactions.
Reporting suspected adverse reactions after drug registration is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all 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 in a cardboard package.
10 tablets in a blister. 3 blisters in a cardboard package.
Prescription status.
Prescription only.
Manufacturer.
LLC "KUSUM PHARM".
Manufacturer's location and address of business activity.
40020, Ukraine, Sumy Oblast, Sumy, Skryabina St., 54.
or
Manufacturer.
LLC "GLEDPHARM LTD".
Manufacturer's location and address of business activity.
40020, Ukraine, Sumy Oblast, Sumy, Hryhoriy Davydovskoho St., 54.