Pantocar

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PANTOCAR® (PANTOCAR)

Composition:

Active substance: pantoprazole;

One enteric-coated tablet contains sodium pantoprazole sesquihydrate equivalent to pantoprazole 40 mg;

Excipients: anhydrous sodium carbonate, pregelatinized starch, microcrystalline cellulose, talc, magnesium stearate, colloidal anhydrous silicon dioxide, sodium hydroxide, hypromellose, polyethylene glycol 6000, titanium dioxide (E 171), yellow iron oxide (E 172), Eudragit L30 D-55 (copolymer of methacrylic acid and ethyl acrylate (1:1), containing 0.7% sodium lauryl sulfate and 2.3% polysorbate 80).

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties: yellow enteric-coated, round, biconvex tablets.

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 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. Most patients become symptom-free within 2 weeks. The use of pantoprazole, as well as other proton pump inhibitors and H₂-receptor antagonists, reduces gastric acidity and thus 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 acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is equivalent following oral and intravenous administration.

With pantoprazole use, fasting gastrin levels increase. With short-term use, these levels usually do not exceed the upper limit of normal. With long-term treatment, gastrin levels typically double. Excessive increases, however, occur only in isolated cases. As a consequence, mild or moderate increases in gastric enterochromaffin-like (ECL) cells (similar to adenomatoid hyperplasia) may occasionally be observed during prolonged treatment. However, according to available studies, the development of precursor cells of neuroendocrine tumors (atypical hyperplasia) or gastric neuroendocrine tumors, which were observed in animal studies, has not been reported in humans.

Based on animal studies, a potential 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 concentrations are 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; plasma concentrations remain stable with repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. Over the dose range of 10 to 80 mg, the plasma pharmacokinetics of pantoprazole remain linear, both after oral administration and intravenous infusion. Absolute bioavailability of the tablets is approximately 77%. Concomitant food intake does not affect AUC (area under the concentration-time curve) or maximum serum concentration, and thus does not affect bioavailability. However, food intake increases only the variability of the latency period.

Distribution. Protein binding of pantoprazole to serum proteins is about 98%. Volume of distribution is approximately 0.15 L/kg.

Biological transformation. 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.

Elimination. Terminal half-life is about 1 hour, and clearance is 0.1 L/h/kg. A few 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 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 have a functional deficiency in CYP2C19 enzyme activity; these individuals are referred to as slow metabolizers. In such individuals, pantoprazole metabolism is likely catalyzed primarily by the CYP3A4 enzyme. After a single 40 mg dose, the mean area under the plasma concentration-time curve (AUC) was approximately 6 times higher in slow 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.

Renal impairment. No dosage adjustment is recommended for patients with impaired renal function (including patients on dialysis). As in healthy individuals, the half-life of pantoprazole remains 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, and thus 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 about 1.5 times—compared to healthy volunteers.

Elderly patients. The slight increase in AUC and C_max observed in elderly volunteers compared to younger volunteers is not clinically significant.

Children. 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 0.8 or 1.6 mg/kg pantoprazole 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.

• Gastroesophageal reflux disease (GERD) with erosive esophagitis.

Adults.

• Eradication of Helicobacter pylori (H. pylori) in patients with H. pylori-associated gastric and duodenal ulcers, in combination with appropriate antibiotics.
• 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.

Medicinal products whose absorption is pH-dependent. Due to the 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 pH-dependent, 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 (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). Clinical studies have shown that concomitant use of pantoprazole with warfarin or phenprocoumon does not affect the pharmacokinetics of warfarin or phenprocoumon, or the international normalized ratio (INR). However, post-marketing reports have indicated increased INR and prolonged prothrombin time in patients receiving concomitant PPIs and 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. Concurrent use of high-dose methotrexate (e.g., 300 mg) and PPIs has been observed to increase methotrexate blood levels in some patients. Patients receiving high-dose 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 CYP3A4. Studies with drugs that are also metabolized via these pathways—such as carbamazepine, diazepam, glyburide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—have not revealed clinically significant interactions. However, interactions between pantoprazole and other drugs metabolized by this enzyme system cannot be ruled out.

Results from several 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), nor does it affect P-glycoprotein associated with digoxin absorption.

No interaction has been observed with concomitantly administered antacids.

Studies investigating the interaction between pantoprazole and concomitantly administered antibiotics (e.g., clarithromycin, metronidazole, amoxicillin) have not revealed any clinically significant interactions.

Medicinal products that inhibit or induce CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, may increase the systemic exposure to pantoprazole. A dose reduction should be considered 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 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.

Combination therapy. During combination therapy, instructions for medical use of the respective medicinal products should be followed.

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., substantial weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena), as well as in suspected or confirmed gastric ulcer, malignancy must be ruled out.

If symptoms persist despite adequate treatment, additional diagnostic evaluation is required.

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 combination of pantoprazole with atazanavir is necessary, careful clinical monitoring (e.g., measurement of viral load) should be performed in combination with increasing the atazanavir dose to 400 mg along with 100 mg ritonavir. The pantoprazole dose should not exceed 20 mg daily.

Vitamin B12 absorption. In patients with Zollinger-Ellison syndrome and other hypersecretory conditions requiring long-term treatment, pantoprazole—as all drugs that inhibit hydrochloric acid production—may reduce absorption of vitamin B12 (cyanocobalamin) due to the development of hypo- or achlorhydria. This should be considered in patients with weight loss or in the presence of risk factors for reduced vitamin B12 absorption during long-term therapy or if corresponding clinical symptoms occur.

Long-term treatment. Patients undergoing long-term treatment, particularly exceeding one year, should be under regular medical supervision.

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 Pantokar® slightly increases 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, such as pantoprazole, for at least three months—most often after a year of treatment. Hypomagnesemia may initially be asymptomatic but can progress to serious clinical manifestations such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. In most cases, the condition 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 treatment and periodically during therapy.

Bone fractures. Long-term (more than 1 year) high-dose treatment with proton pump inhibitors is associated with a slight increase in the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or those with other risk factors. Observational studies suggest that PPI use increases the overall fracture risk by 10–40%. Some of these fractures may be attributable to other 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). PPI use 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 should be considered. Development of SCLE during previous PPI therapy may increase the risk of recurrence with other PPIs.

The medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., it is practically sodium-free.

Effect on laboratory test results.

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

Use during pregnancy or breastfeeding.

Pregnancy. Clinical experience with the use of this medicinal product in pregnant women is limited. Reproductive toxicity was observed in animal reproductive studies. The potential risk in humans is unknown. Pantokar® should not be used during pregnancy except in cases of clear necessity.

Breastfeeding. Animal studies have shown excretion of pantoprazole in breast milk. Data are available showing excretion of pantoprazole in human breast milk. The decision to discontinue breastfeeding or to discontinue/abstain from using Pantokar® should be based on the benefits of breastfeeding to the child and the benefits of therapy to the mother.

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 taken into account. In such cases, patients should refrain from driving or operating machinery.

Method of Administration and Dosage

Pantokar®, gastro-resistant tablets, should be taken whole, 1 hour before a meal, without chewing or crushing, with water.

Recommended Dosage

Adults and children aged 12 years and older

Treatment of reflux esophagitis

The recommended dose is 1 tablet of Pantokar® 40 mg once daily. In individual cases, the dose may be doubled (2 tablets of Pantokar® 40 mg daily), especially if there is no response to other treatments for reflux esophagitis. Treatment of reflux esophagitis usually requires 4 weeks. If healing is not achieved, an additional 4 weeks of treatment may be necessary.

Adults

Eradication of H. pylori in combination with two antibiotics

In adult patients with gastric or duodenal ulcer and a positive test for H. pylori, eradication of the microorganism should be achieved using combination therapy. Local data on bacterial resistance and national guidelines for the use and selection of appropriate antibacterial agents should be considered. Depending on susceptibility, the following therapeutic regimens may be prescribed for H. pylori eradication in adults:

a) 1 tablet of Pantokar® 40 mg twice daily

• 1000 mg amoxicillin twice daily
• 500 mg clarithromycin twice daily;

b) 1 tablet of Pantokar® 40 mg twice daily

• 400–500 mg metronidazole (or 500 mg tinidazole) twice daily
• 250–500 mg clarithromycin twice daily;

c) 1 tablet of Pantokar® 40 mg twice daily

• 1000 mg amoxicillin twice daily
• 400–500 mg metronidazole (or 500 mg tinidazole) twice daily.

When using combination therapy for H. pylori eradication, the second dose of Pantokar® 40 mg should be taken in the evening, 1 hour before a meal. The treatment duration is 7 days and may be extended for another 7 days, with a total treatment duration not exceeding two weeks. If further treatment with pantoprazole is indicated to ensure ulcer healing, dosage recommendations for gastric and duodenal ulcers should be considered. If combination therapy is not indicated, e.g., in patients with a negative H. pylori test, monotherapy with Pantokar® 40 mg should be used at the dosage specified below.

Treatment of gastric ulcer

1 tablet of Pantokar® 40 mg once daily. In individual cases, the dose may be doubled (2 tablets of Pantokar® 40 mg daily), especially if there is no response to other treatments.

Treatment of gastric ulcer usually requires 4 weeks. If healing is not achieved, an additional 4 weeks of treatment may be necessary.

Treatment of duodenal ulcer

1 tablet of Pantokar® 40 mg once daily. In individual cases, the dose may be doubled (2 tablets of Pantokar® 40 mg daily), especially if there is no response to other treatments.

Treatment of duodenal ulcer usually requires 2 weeks. If healing is not achieved, an additional 2 weeks of treatment may be necessary.

Treatment of Zollinger-Ellison syndrome and other hypersecretory conditions

For long-term treatment of Zollinger-Ellison syndrome and other hypersecretory conditions, the initial daily dose is 80 mg (2 tablets of Pantokar® 40 mg). If necessary, the dose may be subsequently titrated up or down based on gastric acid secretion parameters. Doses exceeding 80 mg daily should be divided into two doses. A temporary increase in dose beyond 160 mg of pantoprazole may be considered, but the duration of such high-dose therapy should be limited to the period required for adequate acid control.

The duration of treatment for Zollinger-Ellison syndrome and other hypersecretory conditions is not limited and depends on clinical necessity.

Patients with hepatic impairment
In patients with severe hepatic impairment, the daily dose should not exceed 20 mg (use another pantoprazole medicinal product). Pantokar® should not be used for H. pylori eradication in combination therapy in patients with moderate to severe hepatic impairment, as there are no data on the efficacy and safety of this use in this patient group.

Patients with renal impairment
Dose adjustment is not required in patients with renal impairment. Pantokar® should not be used for H. pylori eradication in combination therapy in patients with renal impairment, as there are no data on the efficacy and safety of this use in this patient group.

Elderly patients do not require dose adjustment.

Children
Pantokar® is indicated in children aged 12 years and older for the treatment of reflux esophagitis. The drug is not recommended for use in children under 12 years of age, as data on the safety and efficacy of pantoprazole 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 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.

Side effects

Adverse reactions were observed in approximately 5% of patients. The most common adverse reactions were diarrhea and headache (occurring in approximately 1% of patients).

Undesirable effects are classified into the following categories:

Blood and lymphatic system disorders: agranulocytosis, leukopenia, thrombocytopenia, pancytopenia.

Immune system disorders: hypersensitivity reactions (including anaphylactic reactions, anaphylactic shock).

Metabolism and nutrition disorders: hyperlipidemia and increased lipid levels (triglycerides, cholesterol); changes in body weight, hyponatremia, hypomagnesemia (see section "Special precautions"), hypocalcemia¹, hypokalemia.

Psychiatric disorders: sleep disorders, depression (including exacerbation), disorientation (including exacerbation), hallucinations, confusion (particularly in patients predisposed to such disorders, as well as exacerbation of these symptoms if already present).

Nervous system disorders: headache, dizziness, taste disturbances, paraesthesia.

Eye disorders: visual disturbances/blurred vision.

Gastrointestinal disorders: fundic gland polyps (benign), diarrhea, nausea, vomiting, abdominal distension, constipation, dry mouth, abdominal pain and discomfort, microscopic colitis.

Hepatobiliary disorders: increased liver enzymes (transaminases, γ-glutamyl transferase), increased bilirubin levels, hepatocellular injury, jaundice, hepatocellular insufficiency.

Skin and subcutaneous tissue disorders: skin rashes, exanthema, pruritus, urticaria, angioedema, Stevens-Johnson syndrome, Lyell's syndrome, erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special precautions").

Musculoskeletal and connective tissue disorders: fractures of the femur, wrist, spine (see section "Special precautions"), arthralgia, myalgia, muscle spasms².

Renal and urinary disorders: interstitial nephritis (with possible progression to renal failure).

Reproductive system and breast disorders: gynecomastia.

General disorders: asthenia, increased fatigue, malaise, increased body temperature, peripheral edema.

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

Shelf life. 3 years.

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

Keep out of reach of children.

Packaging. 10 tablets per blister; 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Micro Labs Limited.

Manufacturer's address and location of business activity.

92, Sipcot Industrial Complex, Hosur, Tamil Nadu, IN–635 126, India.