Controloc

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CONTROLOC â (CONTROLOC â)

Composition:

Active substance: pantoprazole;

1 tablet contains 45.1 mg of sodium pantoprazole sesquihydrate (equivalent to 40.0 mg of pantoprazole);

Excipients: mannite (E 421); anhydrous sodium carbonate; crospovidone; povidone K 90; calcium stearate;

coating: hypromellose 2910; povidone K 25; titanium dioxide (E 171); yellow iron oxide (E 172); propylene glycol; methacrylic acid copolymer (type A); sodium lauryl sulfate; polysorbate 80; triethyl citrate; brown printing ink (S-1-16350).

Pharmaceutical form. Gastro-resistant tablets.

Main physicochemical properties: yellow, oval, biconvex tablets coated with a film coating, with cores white or almost white, marked with brown ink on one side «Р40».

Pharmacotherapeutic group. Drugs for treatment of acid-related disorders. Proton pump inhibitors. Pantoprazole. ATC code A02BC02.

Pharmacological properties.

Pharmacodynamics
Mechanism of action
Pantoprazole is a substituted benzimidazole that inhibits gastric secretion of hydrochloric acid 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 hydrochloric acid production. Inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, symptoms resolve within 2 weeks. The use of pantoprazole, as well as other proton pump inhibitors 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 hydrochloric acid secretion regardless of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is equivalent following oral and intravenous administration.

Administration of pantoprazole increases fasting gastrin levels. With short-term use, these levels usually do not exceed the upper limit of normal. With long-term treatment, gastrin levels typically double. Marked elevation occurs only in isolated cases. As a consequence, prolonged therapy may occasionally lead to mild or moderate increase in specific enterochromaffin-like (ECL) cells in the stomach (similar to adenomatoid hyperplasia). However, according to studies conducted to date, development of precursor cells of neuroendocrine tumors (atypical hyperplasia) or gastric neuroendocrine tumors, observed in animal studies, has not been reported in humans.

Based on animal study results, the influence of long-term (more than one year) pantoprazole treatment on endocrine parameters of the thyroid gland 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 interfere with diagnostic testing for neuroendocrine tumors. Available published data indicate that proton pump inhibitor therapy should be discontinued for a period of 5 days to 2 weeks prior to measuring CgA levels. 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 maximum plasma concentration is achieved after a single oral dose of 40 mg. On average, peak serum concentration of approximately 2–3 μg/mL is reached within 2.5 hours after administration; plasma concentrations remain stable after repeated dosing. Pharmacokinetic properties do not change after single or repeated administration. Within the dose range of 10 to 80 mg, the pharmacokinetics of pantoprazole in plasma remain linear, both after oral administration and intravenous infusion. Absolute bioavailability of pantoprazole in tablet form is approximately 77%. Concomitant food intake does not affect AUC (area under the concentration-time curve) or peak serum concentration, and thus does not affect bioavailability. Food intake only increases the variability of the latent period.

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

Metabolism
Pantoprazole 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.

Elimination. Terminal half-life is approximately 1 hour, and clearance is 0.1 L/h/kg. Several cases of delayed elimination have been observed. 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 (approximately 80%), the remainder in feces. The main metabolite in both serum and urine is desmethylpantoprazole sulfate conjugate. The half-life of the main metabolite (approximately 1.5 hours) is slightly longer than that of pantoprazole.

Special patient populations

Poor metabolizers
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, the mean area under the plasma concentration-time curve was approximately 6 times higher in poor metabolizers compared to individuals with functionally active CYP2C19 (extensive metabolizers). Mean peak plasma concentration increased by approximately 60%. These findings do not affect pantoprazole dosing.

Renal impairment
No dose adjustment is recommended when administering pantoprazole to patients with impaired renal function (including patients on dialysis). As in healthy volunteers, the elimination 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 elimination half-life increases to 7–9 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 C_max 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 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 was observed between pantoprazole clearance and patient age or body weight. AUC and volume of distribution were comparable to those in adults.

Clinical characteristics.

Indications.

Adults and children aged 12 years and older.

• Gastroesophageal reflux disease (reflux 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 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 (such as atazanavir), whose absorption is dependent on intragastric pH, 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 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 administration of pantoprazole with warfarin or phenprocoumon did not affect the pharmacokinetics of warfarin, phenprocoumon, or the INR (International Normalized Ratio). However, there have been reports of increased INR and prolonged prothrombin time in patients receiving concomitant PPIs and warfarin or phenprocoumon. Increased INR and prolonged prothrombin time may lead to severe bleeding and even death. Therefore, when these drugs are used concomitantly, INR and prothrombin time should be monitored.

Methotrexate. There have been reports that concomitant administration of high-dose methotrexate (e.g., 300 mg) and proton pump inhibitors increases 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 by CYP2C19; other metabolic pathways include oxidation by CYP3A4. Studies with drugs that are also metabolized via these pathways—such as carbamazepine, diazepam, glyburide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—did not reveal clinically significant interactions.

An interaction between pantoprazole and other drugs metabolized via 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), and does not affect P-glycoprotein associated with digoxin absorption.

No interaction has been observed with concomitantly administered antacids.

Studies on the interaction of pantoprazole with concomitantly administered antibiotics (clarithromycin, metronidazole, amoxicillin) have been conducted. No clinically significant interactions were observed between these drugs.

Drugs that inhibit or induce CYP2C19. CYP2C19 inhibitors such as fluvoxamine may increase the systemic exposure to pantoprazole. A dose reduction should be considered for patients receiving long-term, high-dose pantoprazole therapy and for 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 prolonged treatment. If liver enzymes rise, treatment with the drug should be discontinued (see section "Dosage and administration").

Combination therapy
When using combination therapy, the instructions for medical use of the respective medicinal products must be followed.

Gastric malignancies
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 suspected or confirmed gastric ulcer, malignancy must be excluded.

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 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").

Vitamin B12 absorption
In patients with Zollinger–Ellison syndrome and other hypersecretory conditions requiring long-term treatment, pantoprazole—as with 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 low body weight or risk factors for reduced vitamin B12 absorption during long-term therapy, or in the presence of corresponding clinical symptoms.

Long-term treatment
Patients undergoing long-term treatment, particularly exceeding one year, 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
Cases of severe hypomagnesemia have been observed in patients treated with proton pump inhibitors (PPIs), such as pantoprazole, for at least three months, and in most cases after one year. Serious clinical manifestations of hypomagnesemia, which may develop insidiously, include fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias. In cases of hypomagnesemia, the patient's condition usually improved after magnesium replacement therapy 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 starting PPI treatment and periodically during therapy.

Bone fractures
Long-term treatment (more than one year) with high doses of proton pump inhibitors may moderately increase the risk of fractures of the hip, wrist, and spine, particularly in elderly patients or those with other risk factors. Observational studies suggest that the use of proton pump inhibitors may increase the overall fracture risk by 10–40%. Some of these fractures may be attributable to other risk factors. Patients at risk of developing osteoporosis should receive treatment according to current clinical guidelines and should ensure adequate intake of vitamin D and calcium.

Subacute cutaneous lupus erythematosus (SCLE)
The use of proton pump inhibitors 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 Controloc® should be considered. Development of SCLE in patients during previous treatment with proton pump inhibitors may increase the risk of recurrence when using other proton pump inhibitors.

Effect on laboratory test results

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

Use during pregnancy or breastfeeding

Pregnancy
Available data on the use of Controloc® in pregnant women (approximately 300–1000 reports on pregnancy outcomes) indicate no embryonal or fetal/neonatal toxicity of the drug. Reproductive toxicity was observed in animal studies. As a precautionary measure, use of Controloc® in pregnant women should be avoided.

Breastfeeding
Animal studies have shown excretion of pantoprazole into breast milk. There is limited data on excretion of pantoprazole into human breast milk, but such excretion has been reported. Risk to the newborn/infant cannot be excluded. The decision to discontinue breastfeeding or to discontinue/withhold treatment with Controloc® should be made considering the benefits of breastfeeding for the child and the benefits of treatment with Controloc® 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 taken into account (see section "Adverse reactions"). In such cases, driving or operating machinery should be avoided.

Method of Administration and Dosage

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

Recommended Dosage

Adults and children aged 12 years and older

Treatment of reflux esophagitis.

The recommended dose is 1 tablet of Controlloc® 40 mg once daily. In individual cases, the dose may be doubled (2 tablets of Controlloc® 40 mg once daily), particularly if there is no response to treatment with other medications for reflux esophagitis. Treatment of reflux esophagitis usually requires 4 weeks. If this is insufficient, healing may be expected during the following 4 weeks.

Adults

Eradication of H. pylori in combination with two antibiotics.

In adult patients with gastric or duodenal ulcer and a positive H. pylori test, eradication of the microorganism should be achieved using combination therapy. Local data on bacterial resistance and national guidelines on 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 Controlloc® 40 mg twice daily

• 1000 mg amoxicillin twice daily

• 500 mg clarithromycin twice daily;

b) 1 tablet of Controlloc® 40 mg twice daily

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

• 250–500 mg clarithromycin twice daily;

c) 1 tablet of Controlloc® 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 Controlloc® 40 mg should be taken in the evening, 1 hour before a meal. The duration of treatment is 7 days and may be extended for another 7 days. The total duration of treatment should not exceed two weeks. If continued 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 Controlloc® 40 mg should be administered at the dosage specified below.

Treatment of gastric ulcer.

1 tablet of Controlloc® 40 mg once daily. In individual cases, the dose may be doubled (2 tablets of Controlloc® 40 mg once daily), particularly if there is no response to treatment with other medications.

Treatment of gastric ulcer usually requires 4 weeks. If this is insufficient, ulcer healing may be expected during the following 4 weeks.

Treatment of duodenal ulcer.

1 tablet of Controlloc® 40 mg once daily. In individual cases, the dose may be doubled (2 tablets of Controlloc® 40 mg once daily), particularly if there is no response to treatment with other medications.

Treatment of duodenal ulcer usually requires 2 weeks. If this is insufficient, ulcer healing may be expected during the following 2 weeks.

Treatment of Zollinger-Ellison syndrome and other hypersecretory conditions.

For long-term treatment of Zollinger-Ellison syndrome and other pathological hypersecretory conditions, the initial daily dose is 80 mg (2 tablets of Controlloc® 40 mg). If necessary, the dose may subsequently be titrated up or down depending on gastric acid secretion parameters. Doses exceeding 80 mg per day should be divided into two doses. Temporary dose increases beyond 160 mg of pantoprazole may be possible, but the duration of use should be limited only to the period required for adequate acid control.

The duration of treatment for Zollinger-Ellison syndrome and other pathological 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 (1 tablet of Controlloc® 20 mg). Controlloc® should not be used for H. pylori eradication in combination therapy in patients with moderate to severe hepatic impairment, as there are currently no data on the efficacy and safety of such use in this patient group.

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

Elderly patients do not require dose adjustment.

Children. Controlloc® 40 mg 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 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 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 recommendations for specific antidotal therapy.

Adverse Reactions

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

Undesirable effects are classified by frequency of occurrence into the following categories: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1,000 and < 1/100), rare (≥ 1/10,000 and < 1/1,000), very rare (< 1/10,000), and not known (frequency cannot be estimated from the available data).

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

Not known: hyponatremia, hypomagnesemia (see section "Special precautions for use"), hypocalcemia\textsuperscript{1}, hypokalemia.

Psychiatric disorders.

Uncommon: sleep disorders.

Rare: depression (including exacerbation).

Very rare: disorientation (including exacerbation).

Not known: hallucination, confusion (particularly in patients predisposed to such disorders, as well as exacerbation of these symptoms if pre-existing).

Nervous system disorders.

Uncommon: headache, dizziness.

Rare: taste disturbances.

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.

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, angioneurotic edema.

Not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special precautions for use").

Musculoskeletal and connective tissue disorders.

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

Rare: arthralgia, myalgia.

Not known: muscle spasms\textsuperscript{2}.

Renal and urinary disorders.

Not known: interstitial nephritis (with possible progression to renal failure).

Reproductive system and breast disorders.

Rare: gynecomastia.

General disorders.

Uncommon: asthenia, fatigue, malaise.

Rare: increased body temperature, peripheral edema.

\textsuperscript{1} Hypocalcemia occurring simultaneously with hypomagnesemia.

\textsuperscript{2} Muscle spasms as a consequence of electrolyte imbalance.

Shelf life.
3 years.

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

Packaging.
14 tablets per blister; 1 or 2 blisters per cardboard box.

Prescription status.
Prescription only.

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

Manufacturer's name and address.
Lehnitzstrasse 70-98, 16515 Oranienburg, Germany.