Pantoprazole abril

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PANTOPRAZOLE ABRYL (PANTOPRAZOLE ABRYL)

Composition:

Active substance: pantoprazole;

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

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 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 H+-K+-ATPase enzyme, thereby blocking the final step of gastric 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. Increased gastrin secretion is reversible. Since pantoprazole binds to the enzyme distal to the cellular receptor, it can inhibit 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 generally do not exceed the upper limit of normal. With long-term treatment, gastrin levels typically double in most cases. Marked increases occur only in isolated instances. As a consequence, mild or moderate increases in specific enterochromaffin-like (ECL) cells in the stomach (similar to adenomatoid hyperplasia) may occasionally be observed during prolonged therapy. However, according to available research data, the formation of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors, observed in animal studies, has not been observed in humans.

Based on animal study results, the influence of long-term (more than one year) pantoprazole treatment on thyroid gland endocrine parameters cannot be completely 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 affect diagnostic test results for neuroendocrine tumors. Available published data suggest that PPI treatment 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 the normal range.

Pharmacokinetics

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

Distribution. The 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 main metabolic pathway is demethylation via CYP2C19, followed by sulfate conjugation; other metabolic pathways include oxidation via CYP3A4.

Elimination. The terminal half-life is approximately 1 hour, and clearance is 0.1 L/h/kg. Several cases of delayed elimination have been noted. 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 serum and urine is desmethylpantoprazole sulfate conjugate. The half-life of the main metabolite (approximately 1.5 hours) is only slightly longer than that of pantoprazole.

Special patient groups

Poor metabolizers. Approximately 3% of Europeans have low functional activity of the CYP2C19 enzyme—these individuals are referred to as poor metabolizers. In these individuals, pantoprazole metabolism is likely primarily catalyzed by the CYP3A4 enzyme. After a single 40 mg dose of pantoprazole, the mean area under the plasma concentration-time curve (AUC) was approximately 6 times higher in poor metabolizers than in individuals with functionally active CYP2C19 (extensive metabolizers). The mean peak plasma concentration increased by approximately 60%. These findings do not affect pantoprazole dosing.

Renal impairment. No dosage reduction recommendations are required when prescribing pantoprazole to patients with impaired renal function (including patients on dialysis). As in healthy volunteers, the half-life of pantoprazole in these patients 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 half-life of pantoprazole 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. The slight increase in AUC and Cmax 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 between pantoprazole clearance and patient age or body weight was observed. AUC and volume of distribution corresponded to data obtained 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 interactions

Medicinal products whose absorption depends on pH. Due to complete and prolonged inhibition of hydrochloric acid secretion, pantoprazole may affect the absorption of medicinal products for which gastric pH is an important factor 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), 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 administration 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 pathological bleeding and even death. Monitoring of INR and prothrombin time is required when these drugs are used concomitantly.

Methotrexate. There have been reports that concomitant administration of high-dose methotrexate (e.g., 300 mg) and proton pump inhibitors 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; 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—have not revealed clinically significant interactions.

Interactions between pantoprazole and other drugs metabolized via the same enzyme system cannot be excluded.

Results from multiple interaction studies 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), nor does it affect P-glycoprotein associated with digoxin absorption.

No interaction has been observed with concurrently administered antacids.

Interaction studies between pantoprazole and certain antibiotics (clarithromycin, metronidazole, amoxicillin) have also been conducted. No clinically significant interactions were observed.

Drugs that inhibit or induce CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, may increase systemic exposure to pantoprazole. A dose reduction should be considered 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 urine screening tests for tetrahydrocannabinol (THC) have been reported in patients receiving pantoprazole. Alternative confirmatory methods 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, persistent vomiting, dysphagia, hematemesis, anemia, melena), as well as in cases of suspected or confirmed gastric ulcer, malignancy must be ruled out. If symptoms persist despite adequate treatment, further investigations are required.

Hepatic impairment. In patients with severe hepatic impairment, liver enzymes should be monitored regularly. If liver enzymes are elevated, 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. 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), including pantoprazole, for at least three months, and in most cases, after one year. Hypomagnesemia may present with serious clinical manifestations, which may initially be subtle and progress insidiously: fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. Hypomagnesemia may lead to the development of hypocalcemia and/or hypokalemia (see section "Undesirable effects"). In most cases, patient condition improved after magnesium replacement therapy and discontinuation of PPI treatment.

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

Bone fractures. Long-term (more than 1 year) high-dose treatment with proton pump inhibitors may moderately increase the risk of fractures of the hip, wrist, and spine, particularly in elderly patients or in the presence of other risk factors. Observational studies suggest that the use of proton pump inhibitors may increase the overall fracture risk by 10–40%. Some fractures may be attributable to other risk factors. Patients at risk of osteoporosis should receive treatment in accordance with current clinical guidelines and ensure adequate intake of vitamin D and calcium.

Severe cutaneous adverse reactions. Serious cutaneous adverse reactions associated with pantoprazole use have been reported, with unknown frequency (see section "Undesirable effects"), 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 considered.

Subacute cutaneous lupus erythematosus. 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 subacute cutaneous lupus erythematosus during treatment with proton pump inhibitors may increase the risk of recurrence with other proton pump inhibitors.

Effect on laboratory test results. Elevated levels of chromogranin A (CgA) may interfere with diagnostic tests for neuroendocrine tumors. To avoid such interference, pantoprazole treatment should be temporarily discontinued at least 5 days prior to 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 proton pump inhibitor therapy.

Important information on excipients.

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

Use during pregnancy or breastfeeding

Pregnancy. Available data on the use of pantoprazole in pregnant women (approximately 300–1000 pregnancy outcomes reported) indicate no embryonal or fetal/neonatal toxicity. 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. A risk to newborns/infants cannot be excluded. The decision whether 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 the speed of reactions 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 taken into account (see section "Undesirable effects"). 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 if 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 can be titrated up or down depending on gastric acid secretion parameters. Doses exceeding 80 mg daily should be divided into two administrations. A temporary increase of the pantoprazole dose above 160 mg may be considered, but the duration of such treatment 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 acid output level (< 10 mEq/h) within 1 hour.

Preparation for use. Dissolve the powder in 10 mL of the provided 0.9% sodium chloride solution 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 solution with altered physicochemical properties (e.g. change in color, precipitation) must be discarded according to local regulations. The diluted 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. Dose adjustment is not required in patients with renal impairment.

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 "Pharmacokinetics" section, 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 a drug that can be readily removed by dialysis. In cases 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 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 into the following categories: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000), very rare (< 1/10,000), and 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 "not known".

Within each frequency category, adverse reactions are listed in decreasing order of 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: hallucinations, 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 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, 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 result 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, should 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. 3 years.

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

Keep out of reach of children.

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

Prescription status. Prescription only.

Manufacturer. Abhil Laboratories Private Limited.

Manufacturer's address and site of operations.

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