Pantoprazole

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

Composition:

Active substance: pantoprazole;

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

Excipients: mannite, sodium phosphate dodecahydrate.

Medicinal form. Powder for solution for injection.

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

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 H+/K+-ATPase (proton pump) 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. Like other proton pump inhibitors (PPIs) and H2-receptor antagonists, pantoprazole reduces gastric acidity and consequently increases gastrin secretion proportionally to the reduction in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds to the enzyme distal to the cellular receptor, it can inhibit gastric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same following oral or intravenous administration.

Pantoprazole treatment increases fasting gastrin levels. With short-term use, levels usually remain within the upper normal range. With long-term treatment, gastrin levels typically double. Marked elevation occurs only in isolated cases. As a consequence, prolonged treatment may occasionally lead to mild or moderate increase in gastric enterochromaffin-like (ECL) cells (similar to adenomatoid hyperplasia). However, according to studies conducted to date, development of neuroendocrine precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors, observed in animal studies, has not been reported 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 interfere with diagnostic testing for neuroendocrine tumors. Available published data suggest that PPI treatment should be discontinued for a period of 5 days to 2 weeks prior to measuring CgA levels. This allows CgA levels, which may be falsely elevated after PPI therapy, to return to normal ranges.

Pharmacokinetics.

Pharmacokinetic properties do not change after single or repeated administration. Over the dose range of 10 to 80 mg, the pharmacokinetics of pantoprazole in plasma remain 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.

Biological transformation. Pantoprazole is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation via CYP2C19, followed by sulfation; another metabolic pathway involves 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 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%), with the remainder eliminated 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 and 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 compared to individuals with functionally active CYP2C19 (extensive metabolizers). The mean peak plasma concentration increased by about 60%. These findings do not affect pantoprazole dosing recommendations.

Renal impairment. No dosage adjustment is recommended when administering pantoprazole to patients with impaired renal function, including those on dialysis. As in healthy volunteers, the elimination half-life of pantoprazole remains short. Only very small amounts of pantoprazole are removed by dialysis. 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 observed in elderly volunteers compared to younger volunteers is not considered 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 ulcer.
• Zollinger-Ellison syndrome and other hypersecretory conditions.

Contraindications. Hypersensitivity to the active substance, to benzimidazole derivatives, or to 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 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 (such as atazanavir), whose absorption depends on intragastric pH, is not recommended due to a significant reduction in their bioavailability (see section "Special warnings and 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 concomitantly with warfarin or phenprocoumon. Elevated 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 that are also metabolized via these pathways—such as carbamazepine, diazepam, glyburide (glibenclamide), nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—did not reveal clinically significant interactions.

An interaction between pantoprazole and other drugs metabolized via 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). It does not affect P-glycoprotein associated with digoxin absorption.

No interaction has been observed with concomitantly administered antacids.

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

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 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.

Special precautions for use.

Malignant gastric neoplasms. Symptomatic response to pantoprazole may mask symptoms of malignant gastric tumors 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 case of suspected or confirmed gastric ulcer, malignancy must be ruled out.

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

Hepatic impairment. Patients with severe hepatic impairment require regular monitoring of liver enzymes. If liver enzymes increase, treatment with the medicinal product should be discontinued (see section "Posology and method of 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. Treatment with Pantoprazole may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile.

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

Hypomagnesaemia. Rare cases of severe hypomagnesaemia have been reported in patients treated with proton pump inhibitors (PPIs), such as pantoprazole, for at least three months, and in most cases, for over a year. Serious clinical manifestations of hypomagnesaemia, such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, may occur and initially develop insidiously. Hypomagnesaemia may lead to the development of hypocalcaemia and/or hypokalaemia (see section "Undesirable effects"). In cases of hypomagnesaemia (as well as hypocalcaemia and/or hypokalaemia associated with hypomagnesaemia), the condition of most patients 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 medications that may cause hypomagnesaemia (e.g., diuretics), 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 moderately increases the risk of fractures of the hip, wrist, and spine, predominantly in elderly patients or in the presence of other risk factors.

Observational studies indicate that the use of proton pump inhibitors increases the overall risk of fractures by 10–40%. Some fractures may be attributable to other risk factors. Patients at risk of osteoporosis should receive treatment according to current clinical guidelines and should ensure adequate intake of vitamin D and calcium.

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, the patient should immediately consult a physician, who will consider whether discontinuation of Pantoprazole is necessary. Development of subacute cutaneous lupus erythematosus during previous treatment with proton pump inhibitors increases the risk of recurrence when other proton pump inhibitors are used.

Effect on laboratory test results.

Elevated chromogranin A (CgA) levels may interfere with diagnostic testing for neuroendocrine tumors. To avoid such interference, treatment with Pantoprazole should be temporarily discontinued at least 5 days before assessment of CgA levels (see section "Pharmacodynamics"). If CgA and gastrin levels do not return to the normal range after initial measurement, repeat measurements should be performed 14 days after discontinuation of proton pump inhibitor therapy.

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 in pregnant women.

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 treatment should be made taking into account the benefits of breastfeeding for the child and the benefits of treatment 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 only a negligible effect on the ability to drive or operate machinery. However, the possible development of adverse reactions such as dizziness and visual disturbances should be considered (see section "Undesirable effects"). In such cases, driving or operating machinery should be avoided.

Method of Administration and Dosage

The medicinal product 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 Pantoprazole is 80 mg per day. If necessary, the dose may be titrated upward or downward depending on gastric acid secretion parameters. Doses exceeding 80 mg per day should be divided into two administrations. Temporary dose increases of pantoprazole to more than 160 mg may be possible, but duration of use should be limited only to the period required for adequate control of acid secretion.

If rapid reduction of acidity is needed, 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

The powder should be dissolved 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 drug is maintained for 12 hours at 25 °C. From a microbiological standpoint, the diluted solution should be used immediately.

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 portion or drug with altered physicochemical properties (e.g. change in color, presence of precipitate) must be discarded in accordance with local regulations.

The diluted solution should be yellowish and clear.

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

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

Elderly patients do not require dose adjustment.

Children. Pantoprazole for injection powder 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 are presented 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 have been well tolerated. Since pantoprazole is highly protein-bound, it is not readily dialyzable.

In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy should be administered. There are no specific antidotes recommended.

Adverse Reactions

Adverse reactions may be expected in approximately 5% of patients. The most common adverse reaction is phlebitis at the injection site. Diarrhea and headache occurred in about 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 (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), and not known (frequency cannot be estimated from available data).

The frequency of adverse reactions reported during the post-marketing period cannot be determined; therefore, they are listed as having a frequency of "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 nutrition disorders

Rare: hyperlipidemia and increased lipid levels (triglycerides, cholesterol), weight changes.

Not known: hyponatremia, hypomagnesemia (see section "Special precautions for use"), hypocalcemia\textsuperscript{1}, hypokalemia\textsuperscript{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, toxic epidermal necrolysis (Lyell's syndrome), erythema multiforme, photosensitivity, drug reaction with eosinophilia and systemic symptoms (DRESS), 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\textsuperscript{2}.

Renal and urinary disorders

Not known: interstitial 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.

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

\textsuperscript{2} Muscle spasms as a consequence of electrolyte imbalance.

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 should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life. 3 years.

After reconstitution or reconstitution and dilution, the chemical and physical stability of the medicinal product is maintained for 12 hours at 25°C. From a microbiological standpoint, the reconstituted/diluted medicinal product should be used immediately.

Storage conditions.

Store in the original packaging, protected from light, at a temperature not exceeding 25°C.

Keep out of the reach of children.

Packaging.

1 vial or 10 vials in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Hainan Poly Pharm Co., Ltd.

Hainan Poly Pharm Co., Ltd.

Manufacturer's address.

Guilinyang Economic Development Area, Haikou, Hainan Province, 571127, China

Guilinyang Economic Development Area, Haikou, Hainan Province, 571127, China

Marketing Authorization Holder.

M.BIOTECH LIMITED

M.BIOTECH LIMITED

Address of the Marketing Authorization Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom