Panocid

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PANOSED (PANOCID)

Composition:

Active substance: pantoprazole;

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

Excipients: tetrasodium edetate, mannitol, tromethamine.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white or almost white powder.

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, thereby blocking the final step of gastric hydrochloric acid production. Inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. Most patients become symptom-free within 2 weeks. As with other proton pump inhibitors (PPIs) and H₂-receptor antagonists, pantoprazole reduces gastric acidity and consequently increases gastrin secretion proportionally to the reduction in acidity. Increased gastrin secretion is reversible. Since pantoprazole binds to the enzyme distal to the cellular receptor, it can inhibit hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same following oral or 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. Marked elevation occurs only in isolated cases. As a consequence, a small number of patients undergoing prolonged treatment may experience mild or moderate increase in the number of enterochromaffin-like (ECL) cells in the stomach (similar to adenomatoid hyperplasia). However, according to studies conducted to date, development of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors, as observed in animal experiments, has not been observed in humans.

Based on animal studies, a potential effect of long-term (more than 1 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. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels rise. 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, which may otherwise be falsely elevated following PPI treatment.

Pharmacokinetics.

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

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

Biological transformation. The substance is almost exclusively metabolized 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 observed. 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 (about 80%), the remainder in feces. The main metabolite in both plasma and urine is desmethylpantoprazole conjugated with sulfate. 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 CYP3A4. After a single 40 mg dose, 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 dose reduction recommendations are required when prescribing pantoprazole to patients with renal impairment, including those on dialysis. As in healthy volunteers, the half-life of pantoprazole remains short in these patients. 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 accumulation does not occur.

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 plasma concentration (C_max) increases only slightly—by 1.5 times compared to healthy volunteers.

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

Children. After 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 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.

• Gastroesophageal reflux disease (GERD).
• Duodenal ulcer.
• Gastric ulcer.
• Zollinger–Ellison syndrome and other hypersecretory 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 is pH-dependent.

Due to complete and prolonged inhibition of hydrochloric 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 (e.g., atazanavir), whose absorption is dependent on intragastric pH, 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 administration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon, or INR (International Normalized Ratio). However, increased INR and prolonged prothrombin time have been reported in patients receiving concomitant PPIs and 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.

There have been reports of increased methotrexate blood levels 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 extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19, with additional metabolism via other pathways, including oxidation by CYP3A4. Studies with drugs also metabolized by these pathways—such as carbamazepine, diazepam, glibenclamide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—did not reveal clinically significant interactions.

Interactions with other drugs metabolized by the same enzyme system cannot be ruled out.

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), or CYP2E1 (e.g., ethanol), and does not affect P-glycoprotein associated with digoxin absorption.

No interaction was observed with concomitantly administered antacids.

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

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 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 by these enzyme systems.

Interaction between medicinal products and laboratory tests.
False-positive results in certain urine screening tests for tetrahydrocannabinol (THC) have been reported in patients taking pantoprazole. Alternative testing methods should be considered to confirm results.

Special precautions for use.

Malignant gastric tumors.

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

If symptoms persist despite adequate treatment, further diagnostic evaluation is required.

Hepatic impairment.

Patients with severe hepatic impairment require regular monitoring of liver enzymes. If liver enzymes increase, pantoprazole treatment 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.

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

Sodium.

The product contains less than 1 mmol of sodium (23 mg) per vial, i.e., it is essentially a sodium-free preparation.

Hypomagnesemia.

Rare cases of severe hypomagnesemia have been reported in patients treated with proton pump inhibitors (PPIs), such as pantoprazole, for at least 3 months, and in most cases for over 1 year. Serious clinical manifestations of hypomagnesemia, which may initially develop insidiously, include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. Hypomagnesemia may lead to the development of hypocalcemia and/or hypokalemia (see section "Adverse reactions"). In cases of hypomagnesemia (as well as hypocalcemia and/or hypokalemia associated with hypomagnesemia), patient condition usually improved after magnesium replacement therapy and discontinuation of PPI treatment.

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 measured before starting 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, 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 fractures may be attributable to other risk factors. Patients at risk of osteoporosis should be managed according to current clinical guidelines and should ensure adequate intake of vitamin D and calcium.

Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions associated with pantoprazole use, with unknown frequency of occurrence (see section "Adverse reactions"), 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.

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 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 testing 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.

Use during pregnancy or breastfeeding.

Pregnancy. Available data on pantoprazole use in pregnant women (approximately 300–1000 pregnancy outcome reports) indicate no evidence of embryonal or fetal/neonatal toxicity. 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. Data on excretion of pantoprazole into human breast milk are limited, but such excretion has been reported. A 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 benefits of breastfeeding for the child and the benefits of pantoprazole 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 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 "Adverse reactions"). In such cases, driving or operating machinery should be avoided.

Method of Administration and Dosage

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

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

Gastroesophageal reflux disease, duodenal ulcer, gastric ulcer.

The recommended dose is 40 mg of pantoprazole (1 vial) once daily 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 Panocid is 80 mg per day. If necessary, the dose may be titrated up or down depending on gastric acid secretion parameters. Doses exceeding 80 mg per day should be divided into two administrations. A temporary increase in pantoprazole dose to more than 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.

Dissolve the powder in 10 mL of 0.9% sodium chloride solution provided in the vial. 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.

From a microbiological standpoint, the diluted preparation should be used immediately. If not used immediately, responsibility for the period of practical stability and conditions prior to administration lies with the person administering the drug. However, the physicochemical stability of the diluted preparation is maintained for 12 hours at 25°C and for 24 hours at 2–8°C.

Pantoprazole must not be prepared or mixed with solvents other than those specified above.

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

The vial is intended for single use only. Any unused product or product with altered physicochemical properties (e.g., change in color, presence of precipitate) must be disposed of according to local regulations.

The diluted solution should be clear and yellowish in color.

Hepatic impairment. In patients with severe hepatic impairment, the daily dose should not exceed 20 mg (½ vial of Panocid 40 mg for injection solution) (see section "Special instructions").

Renal impairment. Patients with impaired renal function do not require dose adjustment.

Elderly patients do not require dose adjustment.

Children.

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

Overdose.

Symptoms of overdose are unknown.

Doses up to 240 mg administered intravenously over 2 minutes were well tolerated. Since pantoprazole is extensively 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 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 (≥ 1/1000 and < 1/100), rare (≥ 1/10000 and < 1/1000), very rare (< 1/10000), not known (frequency cannot be estimated from available data).

For all adverse reactions reported during the post-marketing period, frequency cannot be determined; therefore, they are listed as occurring with "not known" frequency.

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), changes in body weight.

Not known: hyponatremia, hypomagnesemia (see section "Special precautions for use"), hypocalcemia^1, hypokalemia^1.

^1 Hypocalcemia and/or hypokalemia may be associated with the development of hypomagnesemia (see section "Special precautions for use").

Psychiatric disorders.

Uncommon: sleep disorders.

Rare: depression (including exacerbation).

Very rare: disorientation (including exacerbation).

Not known: hallucination, confusion (particularly in patients predisposed to such disorders, as well as exacerbation of these symptoms if previously present).

Nervous system disorders.

Uncommon: headache, dizziness.

Rare: taste disturbances.

Not known: paraesthesia.

Eye disorders.

Rare: visual disturbances/blurred vision.

Gastrointestinal disorders.

Common: fundic gland polyps (benign).

Uncommon: diarrhea, nausea, vomiting, flatulence, constipation, dry mouth, abdominal pain and discomfort.

Not known: microscopic colitis.

Hepatobiliary disorders.

Uncommon: increased levels of 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), erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special precautions for use").

Musculoskeletal and connective tissue disorders.

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

Rare: arthralgia, myalgia.

Not known: muscle spasms^2.

^2 Muscle spasms as a result of electrolyte imbalance.

Renal and urinary disorders.

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

Reproductive system and breast disorders.

Rare: gynecomastia.

General disorders.

Common: phlebitis at the injection site.

Uncommon: asthenia, fatigue, malaise.

Rare: increased body temperature, peripheral edema.

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, or their legal representatives, 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.

From a microbiological standpoint, the reconstituted preparation should be used immediately. If not used immediately, the responsibility for the duration of in-use stability and the conditions prior to administration lies with the user. However, the physico-chemical stability of the reconstituted preparation is maintained for 12 hours at 25 °C and for 24 hours at 2–8 °C.

Storage conditions. Store at a temperature not exceeding 30 °C in the original packaging. Keep out of the reach of children.

Packaging. 1, 5, or 20 vials with powder in a cardboard box labeled in Ukrainian.

Prescription status. Prescription only.

Manufacturer.

LABORATORIOS REIG JOFRE, S.A.

Manufacturer's address.

C/Gran Capitán, 10, Sant Joan Despí, Barcelona, 08970, Spain.

Marketing Authorization Holder.

Ananta Medikare Ltd.

Address of the Marketing Authorization Holder.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.