Pantoprazole ananta

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

Composition:

Active substance: pantoprazole;

1 vial contains 45.11 mg of sodium pantoprazole sesquihydrate, equivalent to 40 mg of pantoprazole;

Excipients: hydrochloric acid concentrated, sodium hydroxide, water for injections (not present in the final product).

Pharmaceutical form. Lyophilized powder for solution for injection.

Main physicochemical properties: white or almost white lyophilized powder. Reconstituted solution: clear, yellowish solution, free from visible particles.

Pharmacotherapeutic group. Drugs for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. Pantoprazole.

ATC code A02BC02.

Pharmacological properties.

Pharmacodynamics.

Pantoprazole is a substituted benzimidazole that inhibits gastric hydrochloric acid secretion by specifically blocking proton pumps in 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. The inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. Most patients are relieved of symptoms within 2 weeks. Like other proton pump inhibitors (PPIs) and H2-receptor antagonists, pantoprazole reduces gastric acidity and thereby 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 after oral and intravenous administration of the drug is equivalent.

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 in most cases increase twofold. However, marked elevation occurs only in isolated cases. As a consequence, in some cases during long-term treatment, a mild or moderate increase in the number of enterochromaffin-like cells (ECL cells) in the stomach (similar to adenomatoid hyperplasia) may be observed. However, according to available studies, the formation of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors, which were observed in animal experiments, has not been observed in humans.

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

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. In addition, due to reduced gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may affect test results in the diagnosis of neuroendocrine tumors. Available published data indicate that PPI treatment should be discontinued for a period of 5 days to 2 weeks before measuring CgA levels. This allows CgA levels, which may be falsely elevated after PPI treatment, to return to the normal range.

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 about 2–3 µg/mL is reached within 2.5 hours after administration; the concentration remains stable after 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, both after oral administration and intravenous infusion. Absolute bioavailability of tablets has been established at approximately 77%. Concomitant food intake does not affect AUC (area under the concentration-time curve) or peak serum concentration, and thus does not affect bioavailability. Food intake only increases the variability of the latent period.

Distribution

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

Biotransformation

The substance is almost exclusively metabolized in the liver. The main metabolic pathway is demethylation via CYP2C19, followed by sulfation; other metabolic pathways include oxidation via CYP3A4.

Elimination

The terminal half-life is about 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 (about 80%), the remainder in feces. The main metabolite in both serum and urine is desmethylpantoprazole conjugated with sulfate. The half-life of the main metabolite (about 1.5 hours) is only slightly longer than that of pantoprazole.

Special patient groups

Slow metabolizers. Approximately 3% of Europeans lack functionally active CYP2C19 enzyme; these individuals are referred to as slow metabolizers. In such individuals, pantoprazole metabolism is likely primarily catalyzed by CYP3A4. After a single 40 mg dose, the mean area under the plasma concentration-time curve was approximately 6 times higher in slow 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. There are no recommendations for dose reduction when administering pantoprazole to 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.

Hepatic impairment. Although in patients with liver cirrhosis (Child–Pugh classes A and B), the 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.

Elderly patients. The 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 corresponded to data obtained in adult studies.

Clinical characteristics.

Indications.

• Moderate to severe reflux esophagitis.
• Duodenal ulcer.
• Gastric ulcer.
• Zollinger–Ellison syndrome and other hypersecretory conditions.

Contraindications.

Hypersensitivity to the active substance, to benzimidazole derivatives, or to any component of the medicinal product. Pantoprazole, like other proton pump inhibitors, is contraindicated with atazanavir.

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 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 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 concomitant PPIs and warfarin or phenprocoumon. Elevated INR and prolonged prothrombin time may lead to the development of 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 via CYP2C19; other metabolic pathways include oxidation by CYP3A4. Studies with drugs that are also metabolized via these pathways—such as carbamazepine, diazepam, glibenclamide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—did not reveal clinically significant interactions.

Interactions between pantoprazole and other drugs metabolized by 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 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.

Interaction studies between pantoprazole and certain concomitantly administered 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 cases 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 drug must be discontinued (see section "Dosage and administration").

HIV protease inhibitors
Proton pump inhibitors are not recommended for concomitant use with HIV protease inhibitors (such as atazanavir), whose absorption depends on intragastric pH, 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
Pantoprazole, like other proton pump inhibitors, may increase the number of bacteria normally present in the upper gastrointestinal tract. Treatment with the drug slightly increases the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile.

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

Hypomagnesemia
Cases of severe hypomagnesemia have been reported in patients treated with PPIs, such as pantoprazole, for at least 3 months, and in most cases, for over a 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 of patients usually improved after magnesium replacement therapy and discontinuation of PPI treatment.

For patients planning long-term therapy, or those receiving PPIs concomitantly with digoxin or medications that may cause hypomagnesemia (e.g., diuretics), magnesium levels should be measured before starting PPI treatment and periodically during therapy.

Bone fractures
Proton pump inhibitors, particularly when used at high doses and for long durations (more than 1 year), are associated with a slightly increased risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other risk factors. Observational studies indicate that PPIs increase the overall risk of fractures by 10–40%. Some of these may be attributable to other risk factors. Patients at risk of osteoporosis should receive treatment according to current clinical guidelines and 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 seek immediate medical advice, and discontinuation of PANTOPRAZOLE ANANTA should be considered. Previous exposure to proton pump inhibitors and development of SCLE may increase the risk of recurrence with other PPIs.

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 ANANTA should be temporarily discontinued at least 5 days before CgA assessment (see section "Pharmacodynamics"). If CgA and gastrin levels do not return to normal after initial measurement, repeat testing 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 reports on pregnancy outcomes) indicate no embryonal or fetotoxic/neonatal toxicity of the drug. Reproductive toxicity was observed in animal studies. As a precautionary measure, use of PANTOPRAZOLE ANANTA in pregnant women should be avoided.

Breastfeeding
Animal studies have shown excretion of pantoprazole into breast milk. There is insufficient data on excretion of pantoprazole into human breast milk, although such excretion has been reported. Risk to newborns or infants cannot be excluded. The decision whether to discontinue breastfeeding or to discontinue/abstain from treatment with PANTOPRAZOLE ANANTA should be made taking into account the benefit of breastfeeding for the child and the benefit of treatment with PANTOPRAZOLE ANANTA 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 reaction speed when driving or operating 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.

Method of Administration and Dosage

Adults. The drug should be used in adults as prescribed and under direct medical supervision.

Intravenous administration of pantoprazole 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, a transition from intravenous administration of PANTOPRAZOLE ANANTA to oral pantoprazole therapy should be performed.

Gastroesophageal reflux disease, duodenal ulcer, gastric ulcer.

The recommended dose is 40 mg of pantoprazole (1 vial) daily administered intravenously. In peptic ulcers complicated by gastrointestinal bleeding, for prevention of rebleeding, initially administer pantoprazole 80 mg intravenously as a bolus injection, followed by continuous infusion at 8 mg/hour for 3 days.

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 ANANTA 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. A temporary increase in pantoprazole dose up to 160 mg may be possible; however, 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.

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 mixing 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.

PANTOPRAZOLE ANANTA 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 administration, vials should be visually inspected (particularly for color change or presence of precipitate). The reconstituted solution should be clear and slightly yellow. Any unused portion or drug with altered physicochemical properties (e.g. color change, precipitate formation) must be discarded according to local regulations.

Hepatic impairment. In patients with severe hepatic impairment, the daily dose should not exceed 20 mg (½ vial of PANTOPRAZOLE ANANTA 40 mg lyophilized powder) (see section "Special Warnings and Precautions for Use").

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

Elderly patients. Dose adjustment is not required.

Children. PANTOPRAZOLE ANANTA, powder for injection solution, is not recommended for use in children (under 18 years of age), as safety and efficacy data in this age group are limited. Available pharmacokinetic data are described 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 were well tolerated. Since pantoprazole is extensively protein-bound, it is not readily removable by dialysis.

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

Side effects.

Adverse reactions occurred in approximately 5% of patients. The most common adverse reactions were phlebitis at the injection site. Diarrhea and headache occurred in about 1% of patients.

Undesirable effects are classified by frequency of occurrence as follows:

Common (> 1/100 and < 1/10), uncommon (> 1/1000 and < 1/100), rare (> 1/10,000 and < 1/1000), very rare (< 1/10,000), 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"), hypocalcemia¹, hypokalemia.

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, bloating, constipation, dry mouth, abdominal pain and discomfort.

Not known: microscopic colitis.

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, subacute cutaneous lupus erythematosus (see section "Special precautions").

Musculoskeletal and connective tissue disorders.

Uncommon: fractures of the femur, wrist, spine (see section "Special precautions").

Rare: arthralgia, myalgia.

Not known: muscle spasms².

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.

¹ Hypocalcemia occurring simultaneously with hypomagnesemia.
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.

Pack No. 1: 40 mg powder for solution for injection in a glass vial, 1 vial in a cardboard package.

Pack No. 10: 40 mg powder for solution for injection in a glass vial, 10 vials in a cardboard package.

Prescription status. Prescription only.

Manufacturer.

STERIL-GENE LIFE SCIENCES (P) LTD, India / Steril-Gene Life Sciences (P) Ltd., India.

Manufacturer's address.

No. 45, Mangalam Main Road, Villianur Commune, Puducherry 605110, India.

Marketing authorization holder. JIVDHARA PHARMA PRIVATE LIMITED.

Address of the marketing authorization holder. 504, Block-B, Shiv Angan Complex, Sallaiya, Bhopal, Bhopal, Madhya Pradesh, 462026, India.