Pantralis®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PANTRALIS® (PANTRALIS®)

Composition:

Active substance:
One tablet contains 45.2 mg of sodium pantoprazole sesquihydrate (equivalent to 40 mg of pantoprazole);

Excipients:
anhydrous sodium carbonate, mannite (E 421), sucrose, talc, calcium stearate, silicon dioxide;

Coating:
hypromellose, talc, macrogol, methacrylic acid and ethyl acrylate copolymer dispersion 30% (Eudragit L30D-55) (methacrylic acid and ethyl acrylate copolymer, polysorbate 80, sodium lauryl sulfate), titanium dioxide (E 171), triethyl citrate, iron oxide red (E 172), iron oxide black (E 172); Opacode Black (shellac (E 904), isopropyl alcohol, iron oxide black (E 172), N-butanol, propylene glycol, ammonium hydroxide).

Pharmaceutical form.
Enteric-coated tablets.

Main physicochemical properties:
enteric-coated tablets, oval-shaped, biconvex surface, with imprint “R 40” on one side and smooth on the other, pinkish-brown in color.

Pharmacotherapeutic group.
Drugs for 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 H+-K+-ATPase enzyme, thereby blocking the final step of hydrochloric acid production in the stomach. Inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. Most patients become symptom-free within 2 weeks. The use of pantoprazole, as with other proton pump inhibitors (PPIs) and H2-receptor antagonists, 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.

Administration of pantoprazole increases fasting gastrin levels. With short-term use, these 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 consequence, during prolonged therapy, a slight or moderate increase in the number of enterochromaffin-like cells (ECL cells) in the stomach (resembling adenomatoid hyperplasia) may be observed in some cases. However, formation of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors, as observed in animal experiments, has not been observed in humans.

Based on animal studies, a potential effect of long-term (more than one year) pantoprazole treatment on thyroid 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 approximately 2.5 hours after administration; serum concentration remains stable with repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. Within the dose range of 10 mg 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 or peak serum concentration, and therefore does not affect bioavailability. Food intake only increases variability in the lag time.

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

Biotransformation. 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. The substance is metabolized almost exclusively in the liver. The primary metabolic pathway is demethylation via CYP2C19, followed by sulfation; other pathways include 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 correlate with the much longer duration of effect (acid secretion inhibition).

The majority of pantoprazole metabolites are excreted in urine (approximately 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 (about 1.5 hours) is slightly longer than that of pantoprazole.

Special patient groups.

Poor metabolizers.
Approximately 3% of Europeans have low functional activity of the CYP2C19 enzyme; these individuals are referred to as poor 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 (AUC) 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 recommendations.

Renal impairment.
No dose adjustment recommendations for pantoprazole are required in patients with impaired renal function (including dialysis patients). As in healthy individuals, 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 half-life increases from 7 to 9 hours and AUC increases 5–7 times, peak serum concentration increases only slightly—by 1.5 times—compared to healthy volunteers.

Elderly patients.
A slight increase in AUC and Cmax in elderly volunteers compared to younger volunteers is not clinically significant.

Children.
After a single oral dose of 20 or 40 mg of pantoprazole, AUC and Cmax 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 of 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.

Adults and children aged 12 years and older.

• Moderate to severe reflux esophagitis.

Adults.

• For eradication of Helicobacter pylori (H. pylori) in patients with peptic ulcers caused by this microorganism, in combination with appropriate antibiotics (see section "Dosage and administration").
• Duodenal ulcer.
• Gastric ulcer.
• Zollinger-Ellison syndrome and other pathological hypersecretory conditions.

Contraindications.

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

Interaction with other medicinal products and other forms of interactions.

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 (including 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 pH-dependent, 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).
Co-administration of pantoprazole with phenprocoumon or warfarin did not affect the pharmacokinetics of phenprocoumon, warfarin, or INR (International Normalized Ratio). However, increased INR and prolonged prothrombin time have been reported in patients receiving concomitant treatment with coumarin anticoagulants and PPIs. Elevated INR and prolonged prothrombin time may lead to the development of pathological bleeding and even death. When these drugs are used concomitantly, monitoring of INR and prothrombin time is required.

Methotrexate.
There have been reports of increased blood levels of methotrexate when high-dose methotrexate (e.g., 300 mg) is administered concomitantly with proton pump inhibitors 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 by CYP2C19, with additional metabolism via CYP3A4 and other pathways. Studies with drugs that are also metabolized through these pathways—such as carbamazepine, diazepam, glyburide, nifedipine, phenprocoumon, 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 excluded.

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), nor does it affect P-glycoprotein-mediated absorption of digoxin.

No interaction has been observed with concomitantly administered antacids.

Studies investigating interactions between pantoprazole and certain antibiotics (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 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.

In patients with severe hepatic impairment, liver enzyme function should be monitored regularly during treatment with pantoprazole, especially with long-term use. If liver enzymes increase, treatment with the drug should be discontinued (see section "Dosage and administration").

During combination therapy, instructions for the respective medicinal products must be followed.

Symptomatic response to pantoprazole may mask symptoms of gastric malignancies 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 gastric ulcer or suspected gastric ulcer, malignancy must be ruled out, since treatment with pantoprazole may mask symptoms of malignant ulcer and delay diagnosis. If symptoms persist during continued adequate treatment, further investigations are required.

Concomitant use of pantoprazole with protease inhibitors of HIV (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"). 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, co-administered with 100 mg ritonavir. The pantoprazole dose should not exceed 20 mg daily.

Pantoprazole®, like all antacid drugs, 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, in the presence of risk factors for reduced vitamin B12 absorption during long-term treatment, or in the presence of corresponding clinical symptoms.

Patients undergoing long-term treatment, particularly exceeding 1 year, should remain under medical supervision.

Pantoprazole®, like other proton pump inhibitors (PPIs), 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 and Campylobacter.

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

In patients requiring long-term therapy, and in patients taking PPIs concomitantly with digoxin or medications that may cause hypomagnesemia (e.g., diuretics), serum magnesium levels should be measured before initiating PPI treatment and periodically during treatment.

Long-term treatment (more than 1 year) with high doses of PPIs slightly increases the risk of bone fractures, particularly in elderly patients or in the presence of other risk factors. Observational studies indicate that PPI use increases the overall risk of fractures by 10–40%. Some of these may be attributable to other risk factors. Patients at risk of developing osteoporosis should receive treatment according to current clinical guidelines and should consume adequate amounts of vitamin D and calcium.

The use of PPIs has been associated with very rare cases of development of subacute cutaneous lupus erythematosus. If skin lesions occur, 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 subacute cutaneous lupus erythematosus in patients during prior therapy with proton pump inhibitors may increase the risk of its recurrence when using other PPIs.

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 fetal/neonatal toxicity of the drug. As a precautionary measure, use of Pantoprazole® in pregnant women should be avoided.

Breastfeeding.
There is insufficient data on the excretion of pantoprazole into breast milk. Risk to newborns/infants cannot be excluded.

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 the ability to drive or operate machinery. The possibility of adverse reactions such as dizziness and visual disturbances should be considered (see section "Adverse reactions"). If such reactions occur, patients should refrain from driving or operating machinery.

Method of Administration and Dosage

Pantrolis®, enteric-coated tablets, should be taken whole, 1 hour before a meal, without chewing or crushing, with a small amount of water.

Adults and children aged 12 years and older.

For the treatment of moderate to severe reflux esophagitis .

The recommended dose for adults and children aged 12 years and older is 1 enteric-coated tablet of Pantrolis® 40 mg once daily. In individual cases, the dose may be doubled (2 enteric-coated tablets of Pantrolis® 40 mg daily), especially if there is no response to other medications. Therapeutic effect is usually achieved within 4 weeks; however, if necessary, the duration of treatment may be extended by another 4 weeks.

Adults.

Eradication of Helicobacter pylori ( H. pylori ) .

In adult patients with gastric and duodenal ulcers and a positive test for H. pylori , eradication of the organism is achieved using combination therapy. Depending on microbial sensitivity, the following therapeutic regimens may be used for H. pylori eradication in adults:

a) 1 enteric-coated tablet of Pantrolis® 40 mg twice daily

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

b) 1 enteric-coated tablet of Pantrolis® 40 mg twice daily

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

c) 1 enteric-coated tablet of Pantrolis® 40 mg twice daily

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

During combination therapy for H. pylori eradication, the second tablet of Pantrolis® 40 mg should be taken 1 hour before the evening meal. Combination therapy typically lasts 7 days, but may be extended by another 7 days if necessary (total duration: two weeks). If ulcer healing requires continued treatment with pantoprazole, the recommended doses for continued treatment of gastric and duodenal ulcers should be individually determined.

If combination therapy is not indicated, e.g., in patients with a negative H. pylori test, the following doses are recommended for monotherapy:

for treatment of gastric ulcer : the recommended dose is 1 enteric-coated tablet of Pantrolis® 40 mg once daily. In individual cases, the dose may be doubled (2 enteric-coated tablets of Pantrolis® 40 mg daily), especially if there is no response to other medications. Therapeutic effect is usually achieved within 4 weeks; however, if necessary, the duration of treatment may be extended by another 4 weeks;

for treatment of duodenal ulcer : the recommended dose is 1 enteric-coated tablet of Pantrolis® 40 mg daily. In individual cases, the dose may be doubled (2 enteric-coated tablets of Pantrolis® 40 mg daily), especially if there is no response to other medications. Therapeutic effect is usually achieved within 2 weeks; however, if necessary, the duration of treatment may be extended by another 2 weeks;

for long-term treatment of Zollinger-Ellison syndrome and other pathological hypersecretory conditions : the initial daily dose is 2 enteric-coated tablets of Pantrolis® 40 mg. If necessary, the dose may be subsequently titrated up or down depending on gastric acid secretion levels. If the daily dose exceeds 80 mg of pantoprazole, it should be divided into two doses. A temporary increase in dose up to 160 mg of pantoprazole may be considered, but the duration of such high-dose therapy should be limited to the period required for adequate control of acid secretion.

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

Patients with hepatic impairment .

The daily dose of pantoprazole should not exceed 20 mg in patients with severe hepatic impairment.

Pantrolis® 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 such use in this patient population.

Patients with renal impairment .

Dose adjustment is not required in patients with renal impairment. Pantrolis® 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 such use in this patient population.

Elderly patients .

Elderly patients do not require dose adjustment.

Children.

Use in children under 12 years of age is not recommended, as data on safety and efficacy in this age group are limited.

Overdose.

Symptoms of overdose are unknown. In case of overdose with signs of intoxication, general detoxification measures should be applied.

Adverse Reactions

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

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), and not known (frequency cannot be estimated from available data).

Blood and lymphatic system disorders

Very rare: leucopenia, thrombocytopenia.

Immune system disorders

Very 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.

Psychiatric disorders

Uncommon: sleep disorders.

Rare: depression (with complications).

Very rare: disorientation (with complications).

Not known: hallucination; confusion (especially in patients predisposed to such disorders).

Nervous system disorders

Uncommon: headache, dizziness.

Eye disorders

Rare: visual disturbances/blurred vision.

Gastrointestinal disorders

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

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, angioedema.

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 spasms.

Renal and urinary disorders

Very rare: interstitial nephritis.

Reproductive system and breast disorders

Rare: gynecomastia.

General disorders

Uncommon: asthenia, fatigue, malaise.

Rare: increased body temperature, peripheral edema.

Shelf life.
3 years.

Storage conditions.
Store at temperatures not exceeding 25 °C in the original packaging to protect from light.

Packaging.
7 tablets in a blister; 2 or 4 blisters in a cardboard box.

Prescription status.
Prescription only.

Manufacturer.
Jubilant Generics Limited.

Address.
Village Sikandarpur Bhainswal, Roorkee–Dehradun Highway, Bhagwanpur, Roorkee District Haridwar, Uttarakhand – 247 661, India.

Marketing Authorization Holder.
SANWEZZA LAB GmbH.

Address.
Gewerbeparkstrasse 10, 2nd floor, office, 1220 Vienna, Austria.