Pantopraz

INSTRUCTIONS for medical use of the medicinal product pantopraz (Pantopraz)

Composition:

Active substance: pantoprazole;

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

Excipient: sodium hydroxide.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physico-chemical properties: lyophilized powder from white to almost white in color.

Pharmacotherapeutic group. Drugs for the treatment of acid-related disorders. Proton pump inhibitors. ATC code A02BC02.

Pharmacological properties.

Pharmacodynamics.

Pantoprazole is a substituted benzimidazole that inhibits gastric hydrochloric acid secretion by specifically blocking the proton pumps of parietal cells. Pantoprazole is transformed into its active form in the acidic environment of parietal cells, where it inhibits the enzyme H+-K+-ATPase, thereby blocking the final step of gastric hydrochloric acid production. Inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. Most patients become symptom-free within 2 weeks. As with other proton pump inhibitors (PPIs) and H2-receptor inhibitors, 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 the enzyme distal to the cellular receptor, it can inhibit hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is equivalent following both oral and intravenous administration.

With pantoprazole use, fasting gastrin levels increase. With short-term treatment, gastrin levels in most cases do not exceed the upper limit of normal. With long-term treatment, gastrin levels typically double. However, marked elevation occurs only in isolated cases. As a result, in a small number of cases during prolonged therapy, mild or moderate increase in the number of enterochromaffin-like (ECL) cells in the stomach (similar to adenomatoid hyperplasia) may be observed. However, according to studies conducted to date, the development of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors, observed in animal experiments, has not been observed in humans.

Based on animal studies, an effect of long-term (more than one year) pantoprazole treatment on thyroid gland endocrine parameters cannot be excluded.

Pharmacokinetics.

Absorption. Pantoprazole is rapidly absorbed, and maximum plasma concentration is achieved after a single oral dose of 40 mg. On average, peak serum concentration of approximately 2–3 µg/mL is reached about 2.5 hours after administration; plasma concentrations remain stable with repeated dosing. 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 for both oral and intravenous administration. Absolute bioavailability of tablets is approximately 77%. Concomitant food intake does not affect AUC (area under the concentration-time curve) or peak serum concentration, and therefore does not affect bioavailability. Food intake only increases the variability of the latent period.

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

Elimination. The substance is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation via CYP2C19, followed by sulfation; other metabolic pathways include oxidation via CYP3A4. The terminal elimination 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 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, conjugated with sulfate. The elimination half-life of the main metabolite (approximately 1.5 hours) is slightly longer than that of pantoprazole.

Special patient populations. 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 catalyzed primarily by the CYP3A4 enzyme. After a single 40 mg dose of pantoprazole, the mean area under the plasma concentration-time curve 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.

No dose reduction recommendations are necessary for patients with impaired renal function (including patients on dialysis). As in healthy individuals, the elimination half-life of pantoprazole is short. Only very small amounts of pantoprazole are dialyzed. Although the main metabolite has a moderately prolonged half-life (2–3 hours), elimination remains rapid, so accumulation does not occur.

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, peak serum concentration increases only slightly—by 1.5 times compared to healthy volunteers. The slight increase in AUC and Cmax in elderly volunteers compared to younger volunteers is also not clinically significant.

Children. After a single oral dose of 20 or 40 mg pantoprazole, AUC and Cmax in children aged 5 to 16 years were within the range of corresponding values in adults. After a single intravenous dose of 0.8 or 1.6 mg/kg pantoprazole in 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 conditions.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Effect of pantoprazole on the absorption of other medicinal products. Due to complete and prolonged inhibition of gastric acid secretion, pantoprazole may reduce the absorption of drugs whose bioavailability is pH-dependent (e.g., certain antifungal agents such as ketoconazole, itraconazole, posaconazole, or other drugs such as erlotinib).

HIV drugs (atazanavir). Concomitant use of proton pump inhibitors with atazanavir and other HIV drugs whose absorption is pH-dependent may lead to a significant reduction in their bioavailability and affect efficacy. Therefore, concomitant use of proton pump inhibitors with atazanavir is not recommended.

In cases where 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). Although no interaction was observed during clinical studies when pantoprazole was administered concomitantly with phenprocoumon or warfarin, isolated cases of changes in INR (International Normalized Ratio) have been reported in the post-marketing period. Therefore, patients receiving coumarin anticoagulants (e.g., phenprocoumon and warfarin) should be monitored for prothrombin time/INR upon initiation, discontinuation, or irregular use of pantoprazole. Increased INR and prolonged prothrombin time may lead to pathological bleeding and even death.

Methotrexate. There have been reports that concomitant use of high-dose methotrexate (e.g., 300 mg) and proton pump inhibitors increases methotrexate blood levels in some patients. Patients receiving high-dose methotrexate, such as those with cancer or psoriasis, should temporarily discontinue pantoprazole therapy.

Medicinal products that inhibit or induce CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, may increase the systemic exposure to pantoprazole. Consideration should be given to dose reduction in patients receiving long-term, high-dose pantoprazole therapy and in patients with hepatic impairment. Enzyme inducers affecting CYP2C19 and CYP3A4, such as rifampicin and St John’s wort (Hypericum perforatum), may reduce plasma concentrations of proton pump inhibitors metabolized via these enzyme systems.

Other interactions. Pantoprazole is extensively metabolized in the liver via the cytochrome P450 enzyme system. The main metabolic pathway is demethylation via CYP2C19, with additional metabolism via CYP3A4. Studies with drugs that are also metabolized via these pathways—such as carbamazepine, diazepam, glibenclamide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—have not shown clinically relevant interactions.

Results from multiple studies on potential interactions indicate that pantoprazole does not affect the metabolism of active substances metabolized via CYP1A2 (e.g., caffeine, theophylline), CYP2C9 (e.g., piroxicam, diclofenac, naproxen), CYP2D6 (e.g., metoprolol), or CYP2E1 (e.g., ethanol), and does not affect P-glycoprotein associated with digoxin absorption.

No interaction has been observed with concomitantly administered antacids.

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

Interaction with other drugs metabolized via the enzymatic system cannot be ruled out.

Special precautions for use.

Malignant gastric tumors. Symptomatic response to pantoprazole may mask symptoms of malignant gastric tumors and delay their diagnosis. In the presence of alarm symptoms (e.g., significant unintentional weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena), as well as in suspected or confirmed gastric ulcer, malignancy must be ruled out, as treatment with pantoprazole may mask symptoms and delay diagnosis. If symptoms persist despite adequate therapy, further investigations are required.

Hepatic impairment. Patients with severe hepatic impairment require regular monitoring of liver enzymes. If liver enzymes increase, treatment with the drug should be discontinued.

Concomitant use with atazanavir. Concomitant use of atazanavir with proton pump inhibitors is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). If combination of PPIs with atazanavir is necessary, careful clinical monitoring (e.g., measurement of viral load) should be performed in combination with increased atazanavir dose to 400 mg together with 100 mg ritonavir. The pantoprazole dose should not exceed 20 mg daily.

Gastrointestinal infections caused by bacteria. Pantoprazole, like other proton pump inhibitors, may increase the number of bacteria normally present in the upper gastrointestinal tract. Treatment with the drug may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile.

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

Hypomagnesemia. Cases of severe hypomagnesemia have been observed in patients treated with PPIs such as pantoprazole for at least three months, and in most cases after one year. Serious clinical manifestations of hypomagnesemia, which may develop insidiously, include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. In cases of hypomagnesemia, the condition in most patients improved after magnesium replacement therapy and discontinuation of PPI treatment.

Patients requiring long-term therapy, or those receiving PPIs concomitantly with digoxin or medications that may cause hypomagnesemia (e.g., diuretics), should have serum magnesium levels 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 slightly increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other risk factors. Observational studies indicate that the use of proton pump inhibitors may increase the overall risk of fractures by 10–40%. Some of these fractures may be attributable to other risk factors. Patients at risk of osteoporosis should receive treatment according to current clinical guidelines and ensure adequate intake of vitamin D and calcium.

Subacute cutaneous lupus erythematosus (SCLE). 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 the necessity of discontinuing pantoprazole. Development of SCLE during previous therapy with proton pump inhibitors may increase 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 this 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 have not returned to 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. Experience with use in pregnant women is limited. Reproductive toxicity was observed in animal reproductive studies. The potential risk in humans is unknown. As a precautionary measure, pantoprazole should be avoided during pregnancy.

Breastfeeding. Animal studies have shown excretion of pantoprazole in breast milk. Data are available on excretion of pantoprazole in human breast milk. The decision to discontinue breastfeeding or to discontinue/abstain from pantoprazole therapy should be made considering 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 affect reaction speed when driving or operating machinery. The possibility of adverse reactions such as dizziness and visual disturbances should be considered. In such cases, driving or operating machinery should be avoided.

Method of Administration and Dosage

The medication should be used by adults only 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, whenever clinically feasible, transition from intravenous administration of Pantopraz to oral administration should be performed.

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 pathological conditions.

For long-term treatment of Zollinger-Ellison syndrome and other hypersecretory conditions, the recommended initial dose of Pantopraz 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. A temporary increase in pantoprazole dose up to more than 160 mg may be possible; however, the duration of such treatment should be limited only to the period required for adequate control of acid secretion.

If rapid reduction of acidity 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.

The drug 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 bottles.

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.

Pantopraz 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. Before use, vials should be inspected visually (particularly for changes in color or presence of precipitate).

The diluted solution should be clear and yellowish in color.

Hepatic impairment. In patients with severe hepatic dysfunction, the daily dose should not exceed 20 mg (½ vial of Pantopraz lyophilisate 40 mg).

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

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

Children. Pantopraz is not recommended for use in children (under 18 years of age), as data on safety and efficacy in this age group are limited.

Overdose.

Symptoms of overdose are unknown.

Doses up to 240 mg administered intravenously over 2 minutes were well tolerated. Since pantoprazole is highly protein-bound, it is not a drug that can be easily removed by dialysis.

In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy should be administered. There are no recommendations for specific antidotal treatment.

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 about 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).

Blood and lymphatic system disorders

Rare: agranulocytosis.

Very rare: leukopenia, thrombocytopenia, pancytopenia.

Immune system disorders

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

Metabolism and nutrition disorders

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

Not known: hyponatremia, hypomagnesemia (see section "Special precautions for use"), hypocalcemia\textsuperscript{1}, hypokalemia.

\Psiychiatric disorders*

Uncommon: sleep disorders.

Rare: depression (including exacerbation).

Very rare: confusion (including exacerbation).

Not known: hallucinations, confusion (particularly in patients predisposed to such disorders, as well as exacerbation of these symptoms if pre-existing).

Nervous system disorders

Uncommon: headache, dizziness.

Rare: taste disturbances.

Not known: paraesthesia.

Eye disorders

Rare: visual disturbances/blurred vision.

Gastrointestinal disorders

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

Common: fundic gland polyps (benign).

Hepatobiliary disorders

Uncommon: increased liver enzymes (transaminases, γ-GT).

Rare: increased bilirubin levels.

Not known: hepatocellular injury, jaundice, hepatocellular failure.

Skin and subcutaneous tissue disorders

Uncommon: skin rashes, exanthema, pruritus.

Rare: urticaria, angioneurotic edema.

Not known: Stevens-Johnson syndrome, Lyell's syndrome, erythema multiforme, photosensitivity.

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 and administration site conditions

Common: thrombophlebitis at the injection site.

Uncommon: asthenia, fatigue, malaise.

Rare: increased body temperature, peripheral edema.

\textsuperscript{1} Hypocalcemia concurrent with hypomagnesemia.
\textsuperscript{2} Muscle spasms as a consequence of electrolyte imbalance.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

40 mg of the drug in a glass vial, stoppered with a rubber stopper and sealed with an aluminum crimp cap equipped with a flip-off cap providing first-opening control.

1 vial per cardboard pack.

Prescription category. Prescription only.

Manufacturer.

IMMACULE LIFESCIENCES PRIVATE LIMITED
IMMACULE LIFESCIENCES PRIVATE LIMITED

Manufacturer's address.

Village Thanthewal, Ropar Road, Nalagarh, District Solan, Himachal Pradesh, IN 174101, India

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