Pantoprazole altan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PANTOPRAZOLE ALTAN

Composition:

Active substance: pantoprazole;

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

Excipients: edetate sodium, mannitol (E 421), tromethamine, sodium hydroxide, hydrochloric acid, water for injections.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: white powder.

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 hydrochloric acid secretion by specifically blocking the proton pumps of parietal cells.

In the acidic environment of parietal cells, pantoprazole is converted into its active form and inhibits H+, K+-ATPase, thereby blocking the final stage 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. Like other proton pump inhibitors (PPIs) and H2-receptor antagonists, pantoprazole reduces gastric acidity and consequently increases gastrin levels proportionally to the reduction in acidity. The increase in gastrin is reversible. Since pantoprazole binds to the enzyme distal to cellular receptors, it has the property of inhibiting hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). Oral and intravenous dosage forms provide equivalent therapeutic effects.

Under the influence of pantoprazole, fasting gastrin levels increase. With short-term use, the upper limit of normal is generally not exceeded. With long-term treatment, gastrin levels typically rise approximately two-fold. However, in individual cases, excessive increases in these levels may occur. As a result, in a small proportion of patients undergoing long-term treatment, slight or moderate increases in the number of specific gastric endocrine cells (as seen in adenomatoid hyperplasia) may be observed. However, according to studies conducted to date, the formation of precursor cells of neuroendocrine tumors (atypical hyperplasia) or gastric neuroendocrine tumors, which were observed in animal experiments, has not been observed in humans. According to animal study results, treatment with pantoprazole for more than 1 year may affect endocrine parameters of the thyroid gland.

During therapy with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Serum chromogranin A (CgA) levels also increase due to reduced gastric acidity. Elevated CgA levels may interfere with testing for neuroendocrine tumors.

According to data from scientific publications, it is recommended to discontinue PPI therapy 5 days to 2 weeks before measuring CgA. This allows CgA levels, which are elevated due to PPI therapy, to return to normal.

Pharmacokinetics

Over the dose range of 10 to 80 mg, the plasma kinetics of pantoprazole are linear for both oral and intravenous administration.

Distribution

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

Biotransformation

The substance is almost completely metabolized in the liver. The main metabolic pathway is demethylation via CYP2C19, followed by sulfate conjugation. Other metabolic pathways include oxidation via CYP3A4.

Elimination

The elimination half-life is approximately 1 hour, and clearance is about 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 therapeutic effect (inhibition of hydrochloric acid secretion).

Most metabolites of pantoprazole (about 80%) are excreted by the kidneys, the remainder in feces. The main metabolite in both serum and urine is desmethylpantoprazole sulfate conjugate. The elimination 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.

Patients with renal impairment (including patients on hemodialysis) do not require dose reduction of pantoprazole. As in healthy individuals, the elimination half-life of pantoprazole in these patients is short. Only a very small amount of pantoprazole is dialyzed. Although the half-life of the main metabolite is slightly prolonged (2–3 hours), it is rapidly eliminated and therefore does not accumulate.

Hepatic impairment. Although in patients with liver cirrhosis (Child-Pugh classes A and B) the elimination half-life of the active substance increases to 7–9 hours, and consequently the AUC increases 5–7 times, the maximum plasma concentration of pantoprazole increases only 1.5-fold compared to healthy volunteers.

Elderly patients. A slight increase in AUC and Cmax in elderly patients compared to younger patients is not clinically significant.

Children. After a single oral dose of 20 or 40 mg of pantoprazole, AUC and Cmax in children aged 5 to 16 years were within the range of corresponding values in adults. After a single intravenous administration of pantoprazole at doses of 0.8 or 1.6 mg/kg to children aged 2 to 16 years, no significant relationship 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.

• Gastroesophageal reflux disease (GERD).
• Duodenal ulcer.
• Gastric ulcer.
• 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 is pH-dependent.

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

HIV protease inhibitors.

Concomitant use of pantoprazole with HIV protease inhibitors (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 for use").

If concomitant use of HIV protease inhibitors and PPIs is considered unavoidable, 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 or 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 concomitantly with warfarin or phenprocoumon. Elevated INR and prolonged prothrombin time may lead to pathological bleeding and even fatal outcomes. Monitoring of INR and prothrombin time is required when these drugs are used concomitantly.

Methotrexate.

Concomitant use of high-dose methotrexate (e.g., 300 mg) and PPIs has been associated with increased methotrexate levels in some patients. Therefore, when high-dose methotrexate is administered, for example in the treatment of cancer or psoriasis, temporary discontinuation of pantoprazole may be required.

Other drug interaction studies.

Pantoprazole undergoes extensive hepatic metabolism via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation by CYP2C19; other pathways include oxidation by CYP3A4.

Interaction studies with other medicinal products metabolized via similar pathways—such as carbamazepine, diazepam, glyburide (glibenclamide), nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—did not reveal clinically significant interactions.

Results of some drug interaction studies indicate that pantoprazole does not affect the metabolism of active substances mediated by CYP1A2 (caffeine, theophylline), CYP2C9 (piroxicam, diclofenac, naproxen), CYP2D6 (metoprolol), CYP2E1 (ethanol), and does not influence p-glycoprotein-mediated absorption of digoxin.

Potential interactions with other medicinal products or compounds metabolized by enzymes of the same system cannot be excluded.

No interactions were observed with concomitant use of antacids.

Drug interaction studies were also conducted with concomitant administration of pantoprazole and certain antibiotics (clarithromycin, metronidazole, amoxicillin). No clinically significant interactions were observed.

Medicinal products that inhibit or induce CYP2C19.

Inhibitors of CYP2C19, such as fluvoxamine, may increase systemic exposure to pantoprazole. In patients receiving long-term high-dose pantoprazole therapy or those with hepatic impairment, dose reduction may be required.

Enzyme inducers affecting CYP2C19 and CYP3A4, such as rifampicin and St. John’s wort (Hypericum perforatum), may reduce plasma concentrations of PPIs metabolized by enzymes of the same system.

Special precautions for use.

Malignant gastric tumors.

Symptomatic response to pantoprazole may mask symptoms of gastric malignancies and complicate diagnosis.

In the presence of alarm symptoms (e.g., rapid unintentional weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena) or when gastric ulcer is suspected or confirmed, malignancy must be excluded.

If symptoms persist despite adequate therapy, further investigations are required.

Hepatic impairment.

In patients with severe hepatic impairment, liver enzyme activity should be monitored during treatment. If liver enzymes increase, treatment should be discontinued.

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").

If co-administration of atazanavir with PPIs cannot be avoided, careful clinical monitoring (including viral load) is recommended. The daily dose of pantoprazole should not exceed 20 mg.

Bacterial gastrointestinal infections.

Like other PPIs, pantoprazole may lead to increased bacterial colonization of the upper gastrointestinal tract. Treatment with this drug slightly increases the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile.

Hypomagnesemia.

Severe hypomagnesemia has been reported in patients treated with PPIs such as pantoprazole for at least 3 months, and in most cases after a year of treatment. Serious manifestations of hypomagnesemia may include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias; however, onset may be insidious and symptoms may be overlooked. In most affected patients, condition improved after magnesium replacement therapy and discontinuation of PPI treatment.

In patients expected to receive long-term therapy or those taking PPIs concomitantly with digoxin or other drugs that may cause hypomagnesemia (e.g., diuretics), physicians should consider measuring magnesium levels before initiating PPI therapy and periodically during treatment.

Sodium.

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

Fractures.

Long-term (more than 1 year) treatment with high doses of PPIs increases the risk of fractures of the hip, wrist, and spine, particularly in elderly patients or those with other risk factors.

Observational studies indicate that PPI use increases the overall fracture risk 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.

Serious cutaneous adverse reactions (SCAR).

Serious cutaneous reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS)) have been reported during pantoprazole use, occurring at unknown frequency and potentially leading to severe or fatal outcomes (see section "Adverse reactions").

Patients should be informed about the signs and symptoms of SCAR when prescribed this drug, and closely monitored for the development of skin reactions.

If signs or symptoms of such reactions occur, pantoprazole should be discontinued immediately and alternative therapy considered.

Subacute cutaneous lupus erythematosus (SCLE).

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 attention, and discontinuation of the drug should be considered. Development of SCLE during previous PPI therapy increases the risk of recurrence with other PPIs.

Effect on laboratory test results.

Elevated chromogranin A (CgA) levels may interfere with tests for neuroendocrine tumors. To avoid this interference, pantoprazole therapy should be discontinued at least 5 days before CgA measurement. If CgA and gastrin levels do not normalize after initial testing, the test should be repeated 14 days after discontinuation of PPI therapy.

Use during pregnancy or breastfeeding.

Pregnancy. Experience with use of the drug in pregnant women is limited. Available data in pregnant women (approximately 300–1000 cases) do not indicate malformative or fetal/neonatal toxicity of pantoprazole. Reproductive toxicity was observed in animal reproductive studies. The medicinal product should not be used during pregnancy.

Breastfeeding. Animal studies have shown excretion of pantoprazole into breast milk. Data are available on excretion of pantoprazole into human breast milk. Risk to newborns/infants cannot be excluded. A decision on whether 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 therapy for the woman.

Fertility. No adverse effects of pantoprazole on fertility were observed in animal studies.

Ability to affect reaction speed when driving or operating machinery.

Pantoprazole has no effect or a negligible effect on the ability to drive or operate machinery.

However, adverse reactions such as visual disturbances and dizziness may occur during treatment with this drug. If such reactions occur, patients should not drive or operate machinery.

Method of Administration and Dosage

The medicinal product should be used in adults as prescribed and under the direct supervision of a physician.

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, when clinically feasible, transition from intravenous to oral administration of the drug at a dose of 40 mg should be performed.

Recommended doses.

Gastric ulcer, duodenal ulcer, and reflux esophagitis — 1 vial (40 mg pantoprazole) once daily intravenously.

Long-term treatment of Zollinger–Ellison syndrome and other pathological conditions of hypersecretion.

The initial daily dose of the medicinal product is 80 mg. If necessary, the dose may be titrated upward or downward depending on gastric acid secretion parameters. If doses exceed 80 mg per day, they should be divided into two administrations. Temporary dose increase of pantoprazole up to 160 mg is possible, but 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.

Hepatic impairment.

In patients with severe hepatic impairment, the daily dose should not exceed 20 mg (½ vial of the 40 mg powder preparation).

Renal impairment.

Patients with impaired renal function do not require dose adjustment.

Elderly patients.

Elderly patients do not require dose adjustment.

Preparation for use.

The ready-to-use solution is prepared by dissolving the powder in the vial with 10 mL of 0.9% sodium chloride injection solution. The resulting solution may be administered immediately or after mixing with 100 mL of 0.9% sodium chloride injection solution or 5% dextrose injection solution.

After preparation, the solution should be used within 12 hours. From a microbiological standpoint, the diluted medicinal product should be used immediately.

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

This medicinal product is intended for intravenous administration over 2–15 minutes.

The vial is intended for single use only. Before administration, the vial containing the solution should be visually inspected (particularly for color change and presence of precipitate).

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"; however, dosage recommendations cannot be provided.

Overdose.

Symptoms of overdose in humans have not been described.

Doses up to 240 mg administered intravenously over 2 minutes were well tolerated. Since pantoprazole is extensively protein-bound, it is not significantly eliminated by hemodialysis.

In case of overdose with clinical signs of intoxication, standard therapeutic measures for intoxication should be applied. There are no recommendations for specific therapy.

Adverse Reactions

Adverse reactions may be expected in approximately 5% of patients. The most commonly reported adverse reactions include phlebitis 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 (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders.

Rare: agranulocytosis.

Very rare: leukopenia, thrombocytopenia, pancytopenia.

Gastrointestinal disorders.

Common: epigastric pain, fundic gland polyps (benign).

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

Frequency not known: microscopic colitis.

Hepatobiliary disorders.

Uncommon: increased levels of liver enzymes (transaminases, γ-glutamyl transferase).

Rare: increased bilirubin levels.

Frequency not known: hepatocellular injury, jaundice, hepatocellular failure.

Immune system disorders.

Rare: hypersensitivity reactions (including anaphylactic reactions, anaphylactic shock).

Skin and subcutaneous tissue disorders.

Uncommon: pruritus, skin rashes, exanthema.

Rare: urticaria, angioedema.

Frequency not known: erythema multiforme, Lyell’s syndrome, Stevens–Johnson syndrome, photosensitivity, subacute cutaneous lupus erythematosus, drug reaction with eosinophilia and systemic symptoms (DRESS) (see section "Special precautions").

Musculoskeletal and connective tissue disorders.

Uncommon: fractures of the femur, wrist, spine.

Rare: arthralgia, myalgia.

Frequency not known: muscle spasms (as a result of electrolyte imbalance).

Nervous system disorders.

Uncommon: headache, dizziness.

Rare: taste disturbances.

Frequency not known: paresthesia.

Psychiatric disorders.

Uncommon: sleep disorders.

Rare: depression (including exacerbation).

Very rare: confusion (including exacerbation).

Frequency not known: hallucinations, confusion (especially in patients predisposed to such disorders, as well as exacerbation of these symptoms if already present).

Eye disorders.

Rare: visual disturbances / blurred vision.

Renal and urinary disorders.

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

General disorders.

Common: phlebitis at the injection site.

Uncommon: asthenia, fatigue, malaise.

Rare: increased body temperature, peripheral edema.

Metabolism and nutrition disorders.

Uncommon: hyperlipidemia and increased lipid levels (triglycerides, cholesterol), changes in body weight.

Frequency not known: hyponatremia, hypomagnesemia (see section "Special precautions"), hypocalcemia^1, hypokalemia.

Reproductive system and breast disorders.

Rare: gynecomastia.

^1 Hypocalcemia concurrent with hypomagnesemia.

Shelf life. 1.5 years.

From a microbiological standpoint, the diluted medicinal product should be used immediately. However, the physico-chemical stability of the diluted medicinal product is maintained for 12 hours at 25 °C.

Storage conditions.

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging.

Powder in a vial. 1 or 10 vials per cardboard box.

Prescription status. Prescription only.

Manufacturer.

ALTA PHARMACEUTICALS, S.A.

Manufacturer's address and location of operations.

Calle Constitución, 198-199, Polígono Industrial Monte Boyal, Casarrubios del Monte, Toledo, 45950, Spain.