Controloc

Pharmaceutical form. Gastric-resistant tablets.

Main physicochemical properties: yellow, oval, biconvex tablets coated with a film, with white or almost white cores. Marked with brown ink on one side: "P20". Gastric-resistant tablets should be of uniform shape, color, and size.

Pharmacotherapeutic group. Drugs for the treatment of acid-related disorders. Proton pump inhibitors. Pantoprazole. ATC code A02B C02.

Pharmacological properties.

Pharmacodynamics. Mechanism of action. 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 H+-K+-ATPase enzyme, thus blocking the final stage of hydrochloric acid production in the stomach. Inhibition is dose-dependent and suppresses both basal and stimulated acid secretion. In most patients, symptoms disappear within 2 weeks. The use of pantoprazole, like other proton pump inhibitors (PPIs) and H2-receptor antagonists, reduces gastric acidity and thus increases gastrin secretion proportionally to the decrease in acidity. Increased 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 of oral and intravenous administration of the drug is the same.

Use 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 increase twofold in most cases. Excessive increases occur only in isolated cases. As a consequence, mild or moderate increase in specific endocrine (ECL) cells in the stomach (similar to adenomatoid hyperplasia) may occasionally be observed during long-term treatment. However, according to currently conducted studies, the formation of neuroendocrine tumor precursor cells (atypical hyperplasia) or gastric neuroendocrine tumors 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 gland endocrine parameters cannot be completely ruled out.

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to reduced gastric acidity, chromogranin A (CgA) levels rise. Elevated CgA levels may affect test results when diagnosing neuroendocrine tumors. Available published data indicate that treatment with proton pump inhibitors 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 normal ranges.

Pharmacokinetics. Absorption. Pantoprazole is rapidly absorbed, and maximum plasma concentration is achieved after a single oral dose of 20 mg. On average, maximum serum concentration of about 1–1.5 µg/mL is reached within 2–2.5 hours after administration; concentration remains stable after repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. In the dose range of 10 to 80 mg, pantoprazole pharmacokinetics in plasma remain linear for both oral administration and intravenous infusion. Absolute bioavailability of pantoprazole in tablets is approximately 77%. Simultaneous food intake does not affect AUC (area under the concentration-time curve) or maximum serum concentration, and thus does not affect bioavailability. Food intake only increases the variability of the latent period.

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

Biotransformation. The substance is metabolized almost exclusively in the liver. The main metabolic pathway is demethylation via CYP2C19 with subsequent sulfate conjugation; other metabolic pathways include oxidation via CYP3A4.

Elimination. 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) slightly exceeds that of pantoprazole.

Special patient groups.

Slow metabolizers. About 3% of Europeans have low functional activity of the CYP2C19 enzyme; they are called slow metabolizers. In these individuals, pantoprazole metabolism is likely primarily catalyzed by the CYP3A4 enzyme. After a single 40 mg dose of pantoprazole, the average area under the plasma concentration-time pharmacokinetic curve was approximately 6 times higher in slow metabolizers than in individuals with functionally active CYP2C19 (fast metabolizers). The average peak plasma concentration increased by approximately 60%. These results do not affect pantoprazole dosing.

Renal impairment. No dosage recommendations are available for administering pantoprazole to patients with impaired renal function (including dialysis patients). As in healthy volunteers, the half-life of pantoprazole in these patients is short. Only very small amounts of pantoprazole are dialyzed. Despite the moderately prolonged half-life (2–3 hours) of the main metabolite, 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 3–6 hours and AUC increases 3–5 times, maximum serum concentration increases only slightly—by 1.3 times compared to healthy volunteers.

Elderly patients. Slight increases in AUC and Cmax in elderly volunteers compared to younger volunteers are not clinically significant.

Children. After a single oral dose of 20 or 40 mg pantoprazole, AUC and Cmax in children aged 5 to 16 years were within the range of corresponding values in adults. After a single intravenous administration of pantoprazole at doses of 0.8 or 1.6 mg/kg to children aged 2 to 16 years, no significant relationship between pantoprazole clearance and patient age or body weight was observed. AUC and volume of distribution corresponded to those in adults.

Clinical characteristics.

Indications.

Adults and children aged 12 years and older.

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

Adults.

• Prevention of gastric and duodenal ulcers caused by non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) in high-risk patients who must use NSAIDs long-term.

Contraindications. Hypersensitivity to the active substance, benzimidazole derivatives, or any component of the drug.

Interaction with other medicinal products and other types 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 juice 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 depends on intragastric pH, is not recommended due to 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, increased INR and prolonged prothrombin time have been reported in patients using PPIs concomitantly with warfarin or phenprocoumon. Increased INR and prolonged prothrombin time may lead to pathological bleeding and even death. Therefore, monitoring of INR and prothrombin time is necessary when these drugs are used concomitantly.

Methotrexate. It has been reported that concomitant use of high-dose methotrexate (e.g., 300 mg) and proton pump inhibitors increases methotrexate blood levels in some patients. Patients receiving high-dose methotrexate, e.g., cancer or psoriasis patients, are advised to temporarily discontinue pantoprazole treatment.

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 also metabolized via 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 excluded.

Results of numerous studies on possible 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), CYP2E1 (e.g., ethanol), and does not affect P-glycoprotein associated with digoxin absorption.

No interaction was found with concomitantly administered antacids.

Interaction studies between pantoprazole and certain concomitantly administered antibiotics (clarithromycin, metronidazole, amoxicillin) were conducted. No clinically significant interactions were found between these drugs.

Drugs that inhibit or induce CYP2C19. CYP2C19 inhibitors, such as fluvoxamine, may increase systemic exposure to pantoprazole. Consideration should be given to dose reduction for patients receiving long-term, high-dose pantoprazole therapy and for 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.

Interaction between medicinal products and laboratory tests. False-positive results in certain urine screening tests for tetrahydrocannabinol have been reported in patients taking pantoprazole. Alternative confirmatory testing methods should be considered to confirm positive results.

Special precautions for use.

Hepatic impairment. Patients with severe hepatic impairment should have liver enzyme levels monitored regularly, especially during long-term treatment. If liver enzyme levels increase, treatment with the drug should be discontinued (see section "Dosage and administration").

Concomitant use with NSAIDs.

Use of Controloc® tablets 20 mg for prevention of gastric and duodenal ulcers caused by long-term NSAID use should be limited to patients prone to frequent recurrences of gastric and duodenal ulcers.

Risk assessment is based on individual risk factors, including age (>65 years), history of gastric or duodenal ulcer, and gastrointestinal bleeding.

Malignant gastric tumors. Symptomatic response to pantoprazole may mask symptoms of malignant gastric tumors and delay their diagnosis. In the presence of alarm symptoms (e.g., significant weight loss, recurrent vomiting, dysphagia, hematemesis, anemia, melena), or suspicion or presence of gastric ulcer, malignancy must be ruled out.

If symptoms persist with adequate treatment, further investigation is necessary.

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 significant reduction in their bioavailability (see section "Interaction with other medicinal products and other types of interactions").

Vitamin B12 absorption. In patients with Zollinger-Ellison syndrome and other hypersecretory conditions requiring long-term treatment, pantoprazole, like all drugs that block hydrochloric acid production, may reduce vitamin B12 (cyanocobalamin) absorption due to hypochlorhydria or achlorhydria. This should be considered in patients with weight loss or risk factors for reduced vitamin B12 absorption during long-term treatment, or with corresponding clinical symptoms.

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

Gastrointestinal infections caused by bacteria. Treatment with Controloc® may slightly increase the risk of gastrointestinal infections caused by bacteria such as Salmonella, Campylobacter, or C. difficile.

Hypomagnesemia. Rare cases of severe hypomagnesemia have been reported in patients receiving proton pump inhibitors (PPIs), such as pantoprazole, for at least three months, and in most cases for a year. Serious clinical manifestations of hypomagnesemia may develop insidiously: fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia (see section "Adverse reactions"). In cases of hypomagnesemia (and hypocalcemia and/or hypokalemia associated with hypomagnesemia), patient condition usually improved after replacement corrective therapy with magnesium and discontinuation of PPIs.

Patients requiring long-term therapy, or patients taking PPIs concomitantly with digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), should have magnesium levels determined before starting PPI therapy and periodically during treatment.

Bone fractures. Long-term (more than 1 year) high-dose proton pump inhibitor therapy may moderately increase the risk of hip, wrist, and spine fractures, primarily in elderly patients or those with other risk factors. Observational studies indicate that proton pump inhibitor use may increase overall fracture risk by 10–40%. Some of these may be due to other risk factors. Patients at risk of osteoporosis should receive treatment according to current clinical guidelines and consume adequate vitamin D and calcium.

Severe skin adverse reactions. Severe skin adverse reactions associated with pantoprazole use, with unknown frequency (see section "Adverse reactions"), potentially life-threatening or fatal, such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported. Patients should be informed about signs and symptoms of these skin reactions and closely monitored for their development. If signs and symptoms indicating these reactions appear, pantoprazole use should be immediately discontinued and alternative treatment considered.

Subacute cutaneous lupus erythematosus. Use of proton pump inhibitors has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions, especially in sun-exposed areas, accompanied by arthralgia, occur, the patient should immediately consult a physician who will consider discontinuing Controloc®. Development of subacute cutaneous lupus erythematosus in patients during previous proton pump inhibitor therapy may increase the risk of its development with other proton pump inhibitors.

Effect on laboratory test results.

Elevated chromogranin A (CgA) levels may affect test results when diagnosing neuroendocrine tumors. To avoid such influence, Controloc® treatment should be temporarily discontinued at least 5 days before assessing CgA levels (see section "Pharmacodynamics"). If CgA and gastrin levels do not return to normal after initial measurement, repeat measurements should be performed 14 days after discontinuation of proton pump inhibitor therapy.

Sodium. Controloc® contains less than 1 mmol of sodium (23 mg) per tablet, i.e., is essentially sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy. Available data on pantoprazole use in pregnant women (approximately 300–1000 pregnancy outcomes reported) indicate no embryonal or fetoneonatal toxicity of pantoprazole. Reproductive toxicity was observed in animal studies. As a precaution, use of Controloc® in pregnant women should be avoided.

Breastfeeding. Animal studies have shown excretion of pantoprazole in breast milk. Data on excretion of pantoprazole in human breast milk are insufficient, but such excretion has been reported. Risk to newborns/infants cannot be excluded. The decision to discontinue breastfeeding or discontinue/withhold Controloc® therapy should be made considering the benefits of breastfeeding for the child and the benefits of Controloc® therapy for the woman.

Fertility. Pantoprazole did not impair fertility in animal studies.

Ability to influence reaction speed when driving or operating machinery. Pantoprazole does not affect or has a very slight effect on reaction speed when driving or operating machinery. Possible development 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.

Controloc®, gastric-resistant tablets, should be taken 1 hour before meals, whole, not chewed or crushed, with water.

Recommended dosage.

Adults and children aged 12 years and older.

Symptomatic treatment of gastroesophageal reflux disease.

The recommended dose is 20 mg (1 tablet) of Controloc® per day. Symptoms of heartburn usually resolve within 2–4 weeks. If this period is insufficient, treatment continues for another 4 weeks. After symptom resolution, recurrence of symptoms can be managed on-demand with 20 mg of the drug once daily, taking 1 tablet as needed. Transition to long-term therapy should be considered if adequate symptom control is not achieved with on-demand therapy.

Long-term treatment and prevention of reflux esophagitis relapses.

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

Adults.

Prevention of gastric and duodenal ulcers caused by non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) in high-risk patients requiring long-term NSAID use.

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

Hepatic impairment. Patients with severe hepatic impairment should not exceed a dose of 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 due to limited data on safety and efficacy in this age group.

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 a drug easily removed by dialysis.

In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy should be applied. No recommendations for specific therapy are available.

Adverse reactions.

Adverse reactions may be expected in about 5% of patients.

Adverse effects by frequency of occurrence are classified into the following categories: 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), unknown (frequency cannot be determined from available data).

For all adverse reactions reported during the post-marketing period, frequency cannot be determined, so they are listed as "frequency unknown".

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.

Unknown: hyponatremia, hypomagnesemia (see section "Special precautions for use"), hypocalcemia¹, hypokalemia¹.

Psychiatric disorders.

Uncommon: sleep disorders.

Rare: depression (including exacerbation).

Very rare: disorientation (including exacerbation).

Unknown: hallucinations, confusion (especially in patients predisposed to such disorders, and exacerbation of these symptoms if pre-existing).

Nervous system disorders.

Uncommon: headache, dizziness.

Rare: taste disturbances.

Unknown: paresthesia.

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.

Unknown: microscopic colitis.

Hepatobiliary disorders.

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

Rare: increased bilirubin levels.

Unknown: hepatocyte injury, jaundice, hepatocellular insufficiency.

Skin and subcutaneous tissue disorders.

Uncommon: skin rashes, exanthema, pruritus.

Rare: urticaria, angioneurotic edema.

Unknown: Stevens-Johnson syndrome, Lyell syndrome (toxic epidermal necrolysis), drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special precautions for use").

Musculoskeletal and connective tissue disorders.

Uncommon: hip, wrist, spine fractures (see section "Special precautions for use").

Rare: arthralgia, myalgia.

Unknown: muscle spasms².

Renal and urinary disorders.

Unknown: tubulointerstitial 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 and/or hypokalemia may be associated with hypomagnesemia (see section "Special precautions for use").

² Muscle spasms as a consequence of electrolyte imbalance.

Reporting suspected adverse reactions

Reporting adverse reactions after drug registration is important. This allows monitoring of the benefit-risk balance of this drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the automated pharmacovigilance information system (https://aisf.dec.gov.ua).

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep out of reach of children!

Packaging. 14 tablets in a blister; 1 blister in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Takeda GmbH, production site Oranienburg, Germany / Takeda GmbH Betriebsstätte Oranienburg, Germany.

Manufacturer's location and address of business premises. Lehnitzstrasse 70-98, 16515, Oranienburg, Germany.