Pantoprazole

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PANTOPRAZOLE

Composition:

Active substance: pantoprazole;

One tablet contains pantoprazole sodium sesquihydrate equivalent to 20 mg of pantoprazole;

Excipients: anhydrous sodium carbonate, mannitol (E 421), sucrose, talc, calcium stearate, silicon dioxide, hypromellose, macrogol, methacrylate copolymer (type A), triethyl citrate, titanium dioxide (E 171), iron oxide red (E 172), iron oxide black (E 172), Opacode black ink (shellac, isopropyl alcohol, iron oxide (E 172), butyl alcohol, propylene glycol, ammonium hydroxide).

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties: light pink to pinkish-brown, biconvex, oval-shaped tablets coated with an enteric coating, marked "P20" on one side and smooth on the other.

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 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, thus blocking the final step of gastric acid production. Inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. Most patients are relieved of symptoms within 2 weeks. The use of pantoprazole, as well as other proton pump inhibitors (PPIs) and H₂-receptor antagonists, reduces gastric acidity and thereby 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 independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same following oral or intravenous administration.

Pantoprazole increases fasting gastrin levels. With short-term use, gastrin levels usually do not exceed the upper limit of normal. With long-term treatment, gastrin levels typically double. Marked increases occur only in isolated cases. 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 studies conducted to date, the development of neuroendocrine tumor precursors (atypical hyperplasia) or gastric neuroendocrine tumors, which were observed in animal studies, has not been observed in humans.

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

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. In addition, due to decreased gastric acidity, chromogranin A (CgA) levels rise. 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 to return to the normal range, as they may be falsely elevated after PPI treatment.

Pharmacokinetics.

Absorption.

Pantoprazole is rapidly absorbed, and maximum plasma concentration (C_max) is achieved after a single oral dose of 20 mg. On average, peak serum concentration of about 1–1.5 µg/mL is reached within 2–2.5 hours after administration; concentrations remain stable after repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. In the dose range of 10–80 mg, the pharmacokinetics of pantoprazole in plasma remain linear, both after oral administration and intravenous infusion. Absolute bioavailability of tablets is approximately 77%. Concomitant food intake does not affect AUC (area under the concentration-time curve) or C_max, and thus does not affect bioavailability. However, food intake increases only the variability of the latency 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 sulfate conjugation; another metabolic pathway involves oxidation via CYP3A4. The terminal 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 reflect 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 sulfate conjugate. The half-life of the main metabolite (about 1.5 hours) is slightly longer than that of pantoprazole.

Special patient groups.

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, mean AUC was approximately 6 times higher in poor metabolizers than in individuals with functionally active CYP2C19 (extensive metabolizers). Mean C_max increased by about 60%. These findings do not affect pantoprazole dosing.

Renal impairment.

No dosage adjustment is recommended for patients with renal impairment (including patients on dialysis). As in healthy individuals, the elimination half-life of pantoprazole is short. Only a very small amount of pantoprazole is 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 elimination half-life increases to 3–6 hours and AUC increases 3–5 times, C_max increases only slightly—by 1.5 times compared to healthy volunteers.

Elderly patients.

A slight increase in AUC and C_max in elderly volunteers compared to younger volunteers is also not clinically significant.

Pediatric patients.

After a single oral dose of 20 or 40 mg pantoprazole, AUC and C_max in children aged 5 to 16 years were within the range observed in adults. After a single intravenous dose of pantoprazole at 0.8 or 1.6 mg/kg in children aged 2 to 16 years, no significant relationship between pantoprazole clearance and age or body weight was observed. AUC and volume of distribution corresponded to data obtained in adult studies.

Clinical characteristics.

Indications.

Adults and children aged 12 years and older.

• Symptomatic treatment of gastroesophageal reflux disease.
• Long-term treatment and prevention of relapse of reflux esophagitis.

Adults.

• Prevention of gastric and duodenal ulceration associated with the use of non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) in patients at risk who require long-term NSAID therapy.

Contraindications.

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

Interaction with other medicinal products and other forms of interactions.

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

HIV protease inhibitors (atazanavir). Concomitant use of PPIs with atazanavir and other antiretroviral drugs whose absorption is pH-dependent may lead to a significant reduction in their bioavailability and affect their efficacy. Therefore, concomitant use of PPIs with atazanavir is not recommended. If concomitant use of HIV protease inhibitors with PPIs 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 co-administered with phenprocoumon and warfarin, isolated cases of changes in INR (International Normalized Ratio) and prolonged prothrombin time have been reported in the post-marketing period in patients receiving PPIs concomitantly with warfarin or phenprocoumon. Increased INR and prolonged prothrombin time may lead to pathological bleeding and even fatal outcomes. Therefore, patients receiving coumarin anticoagulants (e.g., phenprocoumon and warfarin) should be monitored for prothrombin time/INR when starting, stopping, or irregularly taking pantoprazole.

Metotrexate. It has been demonstrated that concomitant administration of high-dose methotrexate (e.g., 300 mg) and PPIs 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, with additional metabolism via other pathways, including oxidation by CYP3A4. Studies with drugs also metabolized through these pathways—such as carbamazepine, diazepam, glyburide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—did not reveal clinically significant interactions.

Interaction between pantoprazole and other drugs metabolized via the same enzyme system cannot be ruled out.

Results from multiple interaction studies 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). Pantoprazole also does not affect

P-glycoprotein, which mediates digoxin absorption.

No interaction has been observed with concomitantly administered antacids.

Studies on the interaction of pantoprazole with certain concomitantly administered antibiotics (clarithromycin, metronidazole, amoxicillin) have 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. The need for 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.

Special precautions for use.

Hepatic impairment.

Patients with severe impairment of liver function should have regular monitoring of liver enzymes, especially during long-term treatment. If liver enzyme levels increase, treatment with the medicinal product should be discontinued.

Concomitant use with NSAIDs.

The use of Pantoprazole 20 mg tablets for prevention of gastric and duodenal ulcers induced by long-term NSAID therapy should be limited in patients prone to frequent recurrences of gastric and duodenal ulcers.

Risk assessment should take into account individual risk factors, including age (>65 years), history of gastric or duodenal ulcer, and gastrointestinal bleeding.

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 unintentional weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena), as well as in suspicion of or presence of gastric ulcer, malignancy must be ruled out, because pantoprazole treatment may mask symptoms and delay diagnosis. If symptoms persist despite adequate treatment, further investigations are required.

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 "Interaction with other medicinal products and other forms of interaction").

Vitamin B12 absorption.

Pantoprazole may reduce absorption of vitamin B12 (cyanocobalamin) due to the development of hypo- or achlorhydria. This should be considered in patients with low body weight or risk factors for reduced vitamin B12 absorption during long-term treatment, or in the presence of relevant clinical symptoms.

Long-term treatment.

During long-term treatment, especially exceeding 1 year, patients should be under regular medical supervision.

Gastrointestinal tract infections caused by bacteria.

Pantoprazole, like other PPIs, may increase the number of bacteria normally present in the upper gastrointestinal tract. Treatment with the medicinal product may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella and Campylobacter or C. difficile.

Hypomagnesemia.

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

Patients requiring long-term therapy, or those taking PPIs concomitantly with digoxin or medications that may cause hypomagnesemia (e.g., diuretics), should have serum magnesium levels measured before initiation of PPI therapy and periodically during treatment.

Bone fractures.

Long-term (more than one year) high-dose PPI therapy may slightly increase the risk of fractures of the hip, wrist, and spine, primarily in elderly individuals or in the presence of other risk factors. Observational studies indicate that PPI use may increase the overall fracture risk 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 should ensure adequate intake of vitamin D and calcium.

Subacute cutaneous lupus erythematosus.

The 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 advice, and discontinuation of the medicinal product should be considered. Development of subacute cutaneous lupus erythematosus in patients during prior PPI therapy may increase the risk of recurrence with other PPIs.

Effect on laboratory test results.

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

Excipients.

The tablets contain mannitol, which may have a mild laxative effect.

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 fetoneonatal toxicity of the medicinal product. Reproductive toxicity was observed in animal studies. As a precautionary measure, pantoprazole use in pregnant women should be avoided.

Breastfeeding period.

Animal studies have shown excretion of pantoprazole in breast milk. Data are available on excretion of pantoprazole in human breast milk. The decision on whether to continue/stop breastfeeding or to continue/stop 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 affect reaction speed when driving or operating machinery.

Pantoprazole has no effect or has 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. In such cases, driving or operating machinery should be avoided.

Method of Administration and Dosage

Pantoprazole enteric-coated tablets should be taken whole, 1 hour before a meal. Do not chew or crush the tablets. Swallow with water.

Recommended Dosage

Adults and children aged 12 years and older

Symptomatic treatment of gastroesophageal reflux disease (GERD).

The recommended dose is 20 mg (1 tablet) of Pantoprazole per day. Heartburn symptoms usually resolve within 2–4 weeks. If this period is insufficient, treatment may be continued for an additional 4 weeks. After symptom resolution, recurrence can be managed on-demand by taking 20 mg of the drug as needed.

Long-term treatment and prevention of reflux esophagitis relapses.

For long-term maintenance therapy, the recommended dose is 20 mg (1 tablet) of Pantoprazole per day. During disease exacerbation, the dose may be increased to 40 mg per day. In such cases, Pantoprazole 40 mg tablets are recommended. After resolution of the relapse, the dose can be reduced again to 20 mg per day.

Adults

Prevention of gastric and duodenal ulcers associated with long-term use of non-selective NSAIDs in high-risk patients requiring prolonged NSAID therapy.

The recommended dose is 20 mg (1 tablet) of Pantoprazole per day.

Hepatic impairment. In patients with severe liver dysfunction, the dose should not exceed 20 mg (1 tablet) per day.

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

Elderly patients do not require dose adjustment.

Children

The drug is not recommended for children under 12 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 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 or recommended specific treatments.

Adverse Reactions

Adverse reactions may be expected in approximately 5% of patients. The most common adverse reactions are diarrhea and headache (approximately 1%).

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 (frequency cannot be estimated from available data).

For all adverse reactions reported during the post-marketing period, it is not possible to determine frequency; therefore, they are listed as "frequency not known."

Within each frequency category, adverse reactions are listed in order of decreasing 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), changes in body weight
Frequency not known: hyponatremia, hypomagnesemia (see section "Special precautions"), hypocalcemia^1, hypokalemia

Psychiatric disorders

Uncommon: sleep disorders
Rare: depression (including exacerbation)
Very rare: disorientation (including exacerbation)
Frequency not known: hallucinations, confusion (particularly in patients predisposed to such disorders, and including exacerbation of these symptoms if pre-existing)

Nervous system disorders

Uncommon: headache, dizziness
Rare: taste disturbances
Frequency not known: paraesthesia

Eye disorders

Rare: visual disturbances/blurred vision

Gastrointestinal disorders

Common: fundic gland polyps (benign)
Uncommon: diarrhea, nausea, vomiting, abdominal distension, constipation, dry mouth, abdominal pain and discomfort
Frequency not known: microscopic colitis

Hepatobiliary disorders

Uncommon: increased liver enzymes (transaminases, γ-GT)
Rare: increased bilirubin levels
Frequency not known: hepatocellular injury, jaundice, hepatocellular failure

Skin and subcutaneous tissue disorders

Uncommon: skin rash, exanthema, pruritus
Rare: urticaria, angioneurotic edema
Frequency 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
Frequency not known: muscle spasms^2

Renal and urinary disorders

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

Reproductive system and breast disorders

Rare: gynecomastia

General disorders

Uncommon: asthenia, fatigue, malaise
Rare: increased body temperature, peripheral edema

^1 Hypocalcemia concurrent with hypomagnesemia.
^2 Muscle spasms as a consequence of electrolyte imbalance.

Reporting 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 drug. Healthcare professionals are encouraged to report suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store out of reach of children at a temperature not exceeding 25°C.

Packaging.

10 tablets in aluminum blisters. 1 or 3 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer.

Jubilant Generics Limited.