Protopan

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

Composition:

Active substance: pantoprazole;

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

Excipients: disodium edetate, sodium hydroxide.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: lyophilized porous mass or powder, white to almost white.

Pharmacotherapeutic group. Drugs for the treatment of acid-related disorders. Proton pump inhibitors. Pantoprazole. 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 affects both basal and stimulated acid secretion. In most patients, symptoms resolve within 2 weeks. The use of pantoprazole, as with other proton pump inhibitors (PPIs) and H2-receptor antagonists, reduces gastric acidity and thus increases gastrin secretion proportionally to the reduction in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds the enzyme distal to the cellular receptor, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect of oral and intravenous administration of the drug is equivalent.

Pantoprazole use increases fasting gastrin levels. With short-term use, these levels mostly remain within the upper normal range. With long-term treatment, gastrin levels typically double in most cases. Marked increases occur only occasionally. As a consequence, mild or moderate increases in specific enterochromaffin-like (ECL) cells in the stomach may occasionally be observed during prolonged treatment (similar to adenomatoid hyperplasia). However, according to available research data, the development of neuroendocrine tumor precursor cells (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 endocrine parameters cannot be entirely ruled out.

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. Published data indicate that treatment with proton pump inhibitors should be discontinued 5–14 days before measuring CgA levels. This allows CgA levels, which may be falsely elevated after PPI treatment, to return to normal ranges.

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.

Biotransformation. The substance is metabolized almost exclusively in the liver. The primary 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 reported. 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 pharmacological effect (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 (approximately 1.5 hours) is slightly longer than that of pantoprazole.

Special patient groups

Poor metabolizers. Approximately 3% of Europeans have low functional activity of the enzyme CYP2C19 — these individuals are referred to as poor metabolizers. In such individuals, pantoprazole metabolism is likely primarily catalyzed by CYP3A4. 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 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 recommendations.

Renal impairment. No dose 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 in these patients. 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 no accumulation occurs.

Hepatic impairment. Although in patients with liver cirrhosis (Child-Pugh classes A and B), the elimination half-life increases to 7–9 hours and AUC increases 5–7 times, the maximum serum concentration 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.

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 comparable to those observed in adult studies.

Clinical Characteristics

Indications

• Gastroesophageal reflux disease (GERD).
• Gastric and duodenal ulcers.
• Zollinger-Ellison syndrome and other hypersecretory pathological conditions.

Contraindications
Hypersensitivity to the active substance, benzimidazole derivatives, or any excipient of the medicinal product.

Interaction with other medicinal products and other forms of interaction

Medicinal products whose absorption depends on pH. Due to complete and prolonged inhibition of gastric acid secretion, pantoprazole may affect the absorption of medicinal products for which gastric 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), 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 proton pump inhibitors 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 PPIs together with warfarin or phenprocoumon. Elevated INR and prolonged prothrombin time may lead to pathological bleeding and even death. In cases of such concomitant use, monitoring of INR and prothrombin time is required.

Methotrexate. There have been reports that concomitant administration of high doses of methotrexate (e.g., 300 mg) and proton pump inhibitors increases blood levels of methotrexate 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; other metabolic pathways include oxidation by CYP3A4. Studies with drugs 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 drugs metabolized via 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), nor does it affect P-glycoprotein associated with digoxin absorption.

No interaction was observed with concurrently administered antacids.

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

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 on laboratory test results. False-positive results in certain urine screening tests for tetrahydrocannabinol (THC) have been reported in patients receiving pantoprazole. An alternative confirmatory method should be considered to verify positive 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), or when suspicion or presence of gastric ulcer exists, malignancy must be ruled out. If symptoms persist despite adequate treatment, further investigations are required.

Hepatic impairment. In patients with severe hepatic dysfunction, liver enzyme levels should be monitored regularly. If liver enzymes are elevated, pantoprazole treatment must 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. The medicinal product 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 reported in patients treated with 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 hypomagnesemia, which may develop insidiously, include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. Hypomagnesemia may lead to the development of hypocalcemia and/or hypokalemia (see section "Adverse reactions"). In most cases, patient condition improved after magnesium replacement therapy and discontinuation of PPI treatment.

In patients requiring long-term therapy and in patients receiving PPIs concomitantly with digoxin or medicinal products that may cause hypomagnesemia (e.g., diuretics), serum magnesium levels should be measured before initiating PPI treatment and periodically during treatment.

Bone fractures. Long-term treatment (more than 1 year) with high doses of proton pump inhibitors 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 the use of proton pump inhibitors may increase the overall risk of fractures by 10–40%. Some fractures may be attributable to other risk factors. Patients at risk of osteoporosis should receive appropriate treatment according to current clinical guidelines and ensure adequate intake of vitamin D and calcium.

Severe cutaneous adverse reactions. Severe cutaneous adverse reactions associated with pantoprazole use have been reported at an unknown frequency (see section "Adverse reactions"), which may be life-threatening or fatal, such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). 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 should be considered.

Subacute cutaneous lupus erythematosus (SCLE). The use of proton pump inhibitors 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, patients should seek immediate medical advice, and discontinuation of the medicinal product should be considered. Previous occurrence of SCLE during treatment with proton pump inhibitors may increase the risk of recurrence with other proton pump inhibitors.

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 measuring CgA levels (see section "Pharmacodynamics"). If CgA and gastrin levels do not return to normal ranges after initial measurement, repeat testing should be performed 14 days after discontinuation of proton pump inhibitor therapy.

Important information about excipients.

Sodium. The medicinal product contains less than 1 mmol sodium (23 mg) per vial, 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 outcome reports) indicate no embryonal or fetal/neonatal 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. There is limited data on excretion of pantoprazole into human breast milk, 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 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 rate while driving or operating machinery. Pantoprazole has no effect or a negligible effect on the ability to drive or operate machinery. However, the possible occurrence of adverse reactions such as dizziness and visual disturbances should be considered (see section "Adverse reactions"). In such cases, driving or operating machinery should be avoided.

Dosage and Administration

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 feasible. Data are available on intravenous treatment duration of up to 7 days. Therefore, as soon as oral administration of pantoprazole becomes possible, 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.

Zollinger–Ellison syndrome and other hypersecretory conditions. For long-term treatment of Zollinger–Ellison syndrome and other hypersecretory conditions, the recommended initial dose of pantoprazole is 80 mg daily. If necessary, the dose may be titrated upward or downward depending on gastric acid secretion parameters. Doses exceeding 80 mg daily should be divided into two administrations. Temporary dose increases above 160 mg may be considered, but duration of use should be limited to the period necessary 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 bags. 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 solution should be used immediately.

The medicinal product must not be prepared or mixed with solvents other than those specified above.

Intravenous administration of the medicinal product should be performed over 2–15 minutes. The vial is intended for single use only. Any unused medicinal product or medicinal product with altered physicochemical properties (e.g. change in color, presence of precipitate) must be discarded 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 the medicinal product) (see section "Special precautions").

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

Elderly patients. Dose adjustment is not required in elderly patients.

Children. The medicinal product is not recommended for use in children (under 18 years of age), as data on safety and efficacy of pantoprazole in this age group are limited. Available data are presented in the section "Pharmacokinetics", but 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 highly protein-bound, it is not readily dialyzable. In cases of overdose with clinical signs of intoxication, symptomatic and supportive therapy should be administered. No specific antidote is available.

Adverse Reactions

Adverse reactions may be expected in approximately 5% of patients. The most common adverse reaction is thrombophlebitis at the injection site. Diarrhea and headache occurred in approximately 1% of patients.

Undesirable effects are classified by frequency of occurrence as follows: 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), and not known (frequency cannot be estimated from available data). For all adverse reactions reported during the post-marketing period, the frequency cannot be determined; therefore, they are listed as "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), changes in body weight.

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

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, and including 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-glutamyl transferase).

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), 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.

Renal and urinary disorders

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

Reproductive system and breast disorders

Rare: gynecomastia.

General disorders and administration site conditions

Common: thrombophlebitis at the injection site.

Uncommon: asthenia, fatigue, malaise.

Rare: increased body temperature, peripheral edema.

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

^2 Muscle spasms as a consequence of electrolyte imbalance.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach and sight of children.

Packaging. 1, 5, or 10 vials per cardboard pack.

Prescription status. Prescription only.

Manufacturer. Abil Laboratories Private Limited.

Manufacturer's address and place of business.

Village Bhagwanpur, Tehsil Dera Bassi, District Sahibzada Ajit Singh Nagar, Punjab – 140507, India.