Instructions for Controloc gastro-resistant tablets 20 mg No. 14
Composition
active ingredient: pantoprazole;
1 tablet contains 22.57 mg of pantoprazole sodium sesquihydrate (equivalent to 20.0 mg of pantoprazole);
excipients: mannitol (E 421); sodium carbonate anhydrous; crospovidone; povidone K 90; calcium stearate;
shell: hypromellose 2910; povidone K 25; titanium dioxide (E 171); iron oxide yellow (E 172); propylene glycol; methacrylate copolymer (type A); sodium lauryl sulfate; polysorbate 80; triethyl citrate; brown ink (S-1-16530).
Dosage form
The pills are gastro-resistant.
Main physicochemical properties: yellow, oval, biconvex tablets, film-coated, with white or almost white cores. Marked in brown ink on one side: "P20". Gastro-resistant tablets should be of uniform shape, color and size.
Pharmacological group
Drugs for the treatment of acid-dependent diseases. Proton pump inhibitors. Pantoprazole. ATC code A02B C02.
Pharmacological properties
Pharmacodynamics
Mechanism of action. Pantoprazole is a substituted benzimidazole that inhibits gastric acid secretion by specific blockade of the proton pumps of parietal cells. Pantoprazole is converted to its active form in the acidic environment of the parietal cells, where it inhibits the enzyme H + -K + -ATPase, i.e. blocks the final stage of gastric acid production. Inhibition is dose-dependent and inhibits both basal and stimulated acid secretion. In most patients, symptoms resolve within 2 weeks. The use of pantoprazole, like other proton pump inhibitors (PPIs) and H 2 -receptor inhibitors, reduces gastric acidity and thus increases gastrin secretion in proportion to the decrease in acidity. The increase in gastrin secretion is reversible. Since pantoprazole binds the enzyme distal to the cell receptor, it can inhibit hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same when the drug is administered orally and intravenously.
Pantoprazole increases fasting gastrin levels. In short-term use, they usually do not exceed the upper limit of normal. In long-term treatment, gastrin levels usually double. Excessive increases occur only in isolated cases. As a result, a slight to moderate increase in specific endocrine (ECL) cells in the stomach (similar to adenomatoid hyperplasia) has sometimes been observed during long-term treatment. However, according to studies conducted to date, the formation of neuroendocrine tumor precursor cells (atypical hyperplasia) or neuroendocrine tumors of the stomach, as observed in animal studies, has not been observed in humans.
Taking into account the results of animal studies, the effect of long-term (more than one year) treatment with pantoprazole on endocrine parameters of the thyroid gland cannot be completely excluded.
During treatment with antisecretory drugs, serum gastrin levels increase in response to decreased acid secretion. In addition, chromogranin A (CgA) levels increase due to decreased gastric acidity. Elevated CgA levels may interfere with diagnostic tests for neuroendocrine tumors. Available evidence suggests that proton pump inhibitor treatment should be discontinued 5 days to 2 weeks before CgA measurements. This allows CgA levels, which may be falsely elevated after PPI treatment, to return to the normal range.
Pharmacokinetics
Absorption. Pantoprazole is rapidly absorbed and peak plasma concentrations are reached after a single oral dose of 20 mg. On average, peak serum concentrations of approximately 1-1.5 μg/ml are reached 2-2.5 hours after administration; concentrations remain constant after multiple administration. The pharmacokinetic properties do not change after single or repeated administration. In the dose range of 10 to 80 mg, the plasma pharmacokinetics of pantoprazole remain linear after both oral and intravenous administration. The absolute bioavailability of pantoprazole tablets has been shown to be approximately 77%. Concomitant food intake does not affect AUC (area under the concentration-time curve) or peak serum concentrations, and therefore bioavailability.
Distribution: The binding of pantoprazole to serum proteins is about 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 by CYP2C19 followed by sulfate conjugation; other metabolic pathways include oxidation by CYP3A4.
The main part of the metabolites of pantoprazole is excreted in the urine (about 80%), the rest is excreted in the 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 not much longer than the half-life of pantoprazole.
Special patient groups.
Poor metabolisers. Approximately 3% of Europeans have a low functional activity of the CYP2C19 enzyme; they are called poor metabolisers. In these individuals, the metabolism of pantoprazole is probably mainly catalysed by the CYP3A4 enzyme. After a single dose of 40 mg pantoprazole, the mean area under the plasma concentration-time curve was approximately 6 times larger in poor metabolisers than in subjects with a functionally active CYP2C19 enzyme (extensive metabolisers). The mean peak plasma concentration was increased by approximately 60%. These findings do not affect the posology of pantoprazole.
Renal impairment. There are no recommendations for dose reduction when prescribing pantoprazole to patients with reduced renal function (including patients on dialysis). As in healthy volunteers, the elimination half-life of pantoprazole is short. Only very small amounts of pantoprazole are dialysable. Although the main metabolite has a moderately long half-life (2-3 hours), elimination is still rapid, so accumulation does not occur.
Hepatic impairment: Although in patients with cirrhosis (Child-Pugh class A and B) the half-life increases to 3-6 hours and the AUC increases 3-5-fold, the maximum serum concentration increases only slightly - 1.3-fold compared to that in healthy volunteers.
Elderly patients: The slight increase in AUC and Cmax in elderly volunteers compared to younger volunteers is also not clinically relevant.
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 the corresponding values in adults. After a single oral dose of 0.8 or 1.6 mg/kg pantoprazole in children aged 2 to 16 years, there was no significant relationship between the clearance of pantoprazole and the patient's age or body weight. The AUC and volume of distribution were similar to those in adults.
Indication
Adults and children from 12 years old.
Symptomatic treatment of gastroesophageal reflux disease.
Long-term treatment and prevention of reflux esophagitis recurrence.
Adults.
Prevention of gastric and duodenal ulcers caused by taking non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk who must use NSAIDs for a long time.
Contraindication
Hypersensitivity to the active substance, benzimidazole derivatives or to any component of the drug.
Interaction with other medicinal products and other types of interactions
Medicinal products whose absorption is pH-dependent: Due to the complete and prolonged inhibition of hydrochloric acid secretion, pantoprazole may affect the absorption of medicinal products for which the pH of the gastric juice is an important factor in their bioavailability (e.g. some antifungals such as ketoconazole, itraconazole, posaconazole or other medicinal products such as erlotinib).
HIV protease inhibitors: The concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir) whose absorption is dependent on intragastric pH is not recommended due to a significant reduction in their bioavailability (see section 4.4).
If concomitant use of HIV protease inhibitors with proton pump inhibitors cannot be avoided, close 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 required.
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 receiving concomitant PPIs and 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 with such concomitant use.
Methotrexate: Concomitant use of high doses of methotrexate (e.g. 300 mg) and proton pump inhibitors has been reported to increase blood levels of methotrexate in some patients. Patients receiving high doses of methotrexate, e.g. patients with cancer or psoriasis, are advised to temporarily discontinue pantoprazole treatment.
Interactions of pantoprazole with other drugs metabolized by the same enzyme system cannot be excluded.
The results of a number of studies on possible 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, ethanol), and does not affect p-glycoprotein, which is associated with the absorption of digoxin.
No interactions with concomitantly administered antacids were identified.
A study of the interaction of pantoprazole with certain antibiotics (clarithromycin, metronidazole, amoxicillin) administered concomitantly has been conducted. Clinically significant interactions between these drugs have been identified.
Medicinal products that inhibit or induce CYP2C19. CYP2C19 inhibitors, such as fluvoxamine, may increase the systemic exposure of pantoprazole. A dose reduction should be considered in patients receiving long-term treatment with high doses of pantoprazole and in patients with impaired liver function. Inducers of enzymes that affect CYP2C19 and CYP3A4, such as rifampicin and St. John's wort (Hypericum perforatum), may reduce the plasma concentration of PPIs metabolised by these enzyme systems.
Application features
Hepatic impairment: Patients with severe hepatic impairment should have their liver enzymes monitored regularly, especially during long-term treatment. If liver enzymes increase, treatment should be discontinued (see section 4.2).
Concomitant use with NSAIDs.
The use of Controloc 20 mg tablets for the prevention of gastric and duodenal ulcers caused by taking NSAIDs for a long time should be limited to patients prone to frequent exacerbations 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.
Gastric malignancies. Symptomatic response to pantoprazole may mask the symptoms of gastric malignancies and delay their diagnosis. In the presence of alarming symptoms (e.g. significant weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia, melena), as well as in the presence or suspicion of gastric ulcer, malignancy should be excluded.
If symptoms persist despite adequate treatment, further examination is necessary.
HIV protease inhibitors: The concomitant use of pantoprazole with HIV protease inhibitors (such as atazanavir) whose absorption is dependent on intragastric pH is not recommended due to a significant reduction in their bioavailability (see section 4.5).
Vitamin B12 absorption. In patients with Zollinger-Ellison syndrome and other hypersecretory pathological conditions requiring long-term treatment, pantoprazole, like all drugs that block the production of hydrochloric acid, may reduce the absorption of vitamin B12 (cyanocobalamin) due to the occurrence of hypo- and achlorhydria. This should be taken into account in patients with low body weight or the presence of risk factors for reduced absorption of vitamin B12 during long-term treatment or in the presence of relevant clinical symptoms.
Long-term treatment. With long-term treatment, especially more 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 and Campylobacter or C. Difficile.
Hypomagnesemia: Severe hypomagnesemia has been reported in patients treated with PPIs such as pantoprazole for at least three months and in most cases for a year. Serious clinical manifestations of hypomagnesemia may occur and may initially be insidious: fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmias. In the case of hypomagnesemia, the majority of patients improved after magnesium replacement therapy and discontinuation of the PPI.
Patients requiring long-term therapy or patients taking PPIs concomitantly with digoxin or drugs that may cause hypomagnesemia (e.g., diuretics) should have their magnesium levels measured before starting PPI treatment and periodically during treatment.
Subacute cutaneous lupus erythematosus. The use of proton pump inhibitors has been associated with very rare cases of subacute cutaneous lupus erythematosus. If lesions occur, especially in areas exposed to sunlight, and this is accompanied by arthralgia, the patient should immediately consult a doctor who will consider the need to discontinue Controloc. The occurrence of subacute cutaneous lupus erythematosus in patients during previous therapy with proton pump inhibitors may increase the risk of its development with the use of other proton pump inhibitors.
Impact on laboratory test results.
Elevated chromogranin A (CgA) levels may interfere with the results of tests used to diagnose neuroendocrine tumors. To avoid this interference, treatment with Controloc should be temporarily discontinued for at least 5 days prior to CgA measurement (see section 5.2). If CgA and gastrin levels have not returned to the normal range after baseline measurement, repeat measurements should be performed 14 days after discontinuation of proton pump inhibitor treatment.
Use during pregnancy or breastfeeding
Pregnancy. Available data on the use of Controloc® in pregnant women (approximately 300-1000 pregnancy outcomes) indicate no embryonal or feto/neonatal toxicity of the drug. Reproductive toxicity has been observed in animal studies. As a precautionary measure, Controloc® should be avoided in pregnant women.
Breastfeeding. Animal studies have shown excretion of pantoprazole in breast milk. There is insufficient information on the excretion of pantoprazole in human milk, but such excretion has been reported. A risk to the newborn/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Controloc® therapy taking into account the benefit of breast-feeding for the child and the benefit of Controloc® therapy for the woman.
Fertility: Pantoprazole did not impair fertility in animal studies.
Ability to influence reaction speed when driving vehicles or other mechanisms
Pantoprazole has no or very little effect on the ability to drive or use machines. It is necessary to take into account the possible development of side effects such as dizziness and visual disturbances (see section "Adverse reactions"). In such cases, you should not drive or use machines.
Method of administration and doses
Controloc®, gastro-resistant tablets, should be taken 1 hour before meals whole, do not chew or crush, and washed down with water.
Recommended dosage.
Adults and children from 12 years old.
Symptomatic treatment of gastroesophageal reflux disease.
The recommended dose is 20 mg (1 tablet) of Controloc per day. Heartburn symptoms usually resolve within 2-4 weeks. If this period is not sufficient, treatment is continued for 4 weeks. After symptoms have resolved, recurrence of symptoms can be controlled by administering 20 mg once daily as needed, taking 1 tablet when needed. Transition to long-term therapy should be considered if symptoms are not adequately controlled with on-demand therapy.
Long-term treatment and prevention of reflux esophagitis recurrence.
For long-term treatment, the maintenance dose is 20 mg (1 tablet) of Controloc per day, with exacerbation of the disease, the dose may be increased to 40 mg per day. In this case, it is recommended to take Controloc 40 mg tablets. After the relapse is eliminated, the dose can be reduced to 20 mg per day.
Adults.
Prevention of gastric and duodenal ulcers caused by taking non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk who must take NSAIDs for a long time.
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 use in children under 12 years of age, as data on the safety and efficacy of the drug for 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 extensively protein bound, it is not readily dialyzable.
In case of overdose with clinical signs of intoxication, symptomatic and supportive therapy is used. There are no recommendations for specific therapy.
Side effects
Adverse reactions can be expected in about 5% of patients. The most common adverse reactions are diarrhea and headache (occurring in about 1% of patients).
For all adverse reactions reported during the post-marketing period, it is not possible to determine the frequency and are therefore indicated as “frequency unknown”.
Within each frequency category, adverse reactions are presented in order of decreasing seriousness.
From the blood and lymphatic system.
Rarely, agranulocytosis.
Very rare: leukopenia, thrombocytopenia, pancytopenia.
From the immune system.
Rare: hypersensitivity reaction (including anaphylactic reactions, anaphylactic shock).
Metabolism and metabolic disorders.
Rare: hyperlipidemia and increased lipid levels (triglycerides, cholesterol), changes in body weight.
Not known: hyponatremia, hypomagnesemia (see section "Special warnings and precautions for use"), hypocalcemia 1 , hypokalemia.
Mental disorders.
Uncommon: sleep disorders.
Rare: depression (especially exacerbation).
Very rare: disorientation (including exacerbation).
Not known: hallucination, confusion (especially in patients with a predisposition to such disorders, as well as exacerbation of these symptoms in case of pre-existing conditions).
From the nervous system.
Uncommon: headache, dizziness.
Rare: taste disturbance.
Not known: paraesthesia.
From the organ of vision.
Rare: visual disturbances/blurred vision.
From the digestive tract.
Common: fundic gland polyps (benign).
Uncommon: diarrhoea, nausea, vomiting, abdominal bloating, constipation, dry mouth, abdominal pain and discomfort.
On the part of the hepatobiliary system.
Uncommon: increased liver enzymes (transaminases, g-GT).
Rare: increased bilirubin levels.
Not known: hepatocyte damage, jaundice, hepatocellular failure.
On the skin and subcutaneous tissue.
Uncommon: skin rash, exanthema, pruritus.
Rare: urticaria, angioedema.
Not known: Stevens-Johnson syndrome, Lyell's syndrome, erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special warnings and precautions for use").
On the part of the musculoskeletal system and connective tissue.
Uncommon: fractures of the hip, wrist, spine (see section "Special warnings and precautions for use").
Rare: Arthralgia, myalgia.
Not known: muscle spasm 2.
On the part of the kidneys and urinary system.
Not known: interstitial nephritis (possible development of renal failure).
From the reproductive system and mammary glands.
Rare: gynecomastia.
General disorders.
Uncommon: asthenia, fatigue, malaise.
Rare: fever, peripheral edema.
1 Hypocalcemia concomitant with hypomagnesemia.
2 Muscle spasm due to electrolyte imbalance.
Expiration date
3 years.
Storage conditions
Does not require special storage conditions. Keep out of the reach of children!
Packaging
14 tablets in a blister; 1 blister in a cardboard box.
Vacation category
According to the recipe.
Producer
Takeda GmbH, production site Oranienburg, Germany / Takeda GmbH Betriebsstätte Oranienburg, Germany.
Address
Lehnitzstrasse 70-98, 16515 Oranienburg, Germany / Lehnitzstrasse 70-98, 16515 Oranienburg, Germany.
