Controlok

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: dry powder, white to off-white in colour.

Diluted solution – clear yellowish solution.

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 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, 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. Use of pantoprazole, as with other proton pump inhibitors (PPIs) and H₂-receptor antagonists, reduces gastric acidity and thereby increases gastrin secretion proportionally to the reduction 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 is equivalent.

Pantoprazole use increases fasting gastrin levels. With short-term use, levels in most cases do not exceed the upper limit of normal. With long-term treatment, gastrin levels increase up to two-fold in most cases. Marked elevation occurs only in isolated cases. As a consequence, mild or moderate increase in specific enterochromaffin-like (ECL) cells in the stomach may occasionally be observed during prolonged treatment (similar to adenomatoid hyperplasia). However, according to current studies, the formation of neuroendocrine tumour precursor cells (atypical hyperplasia) or gastric neuroendocrine tumours, observed in animal studies, 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 completely excluded.

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 increase. Elevated CgA levels may affect diagnostic test results for neuroendocrine tumours. Available published data indicate that PPI treatment 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 range.

Pharmacokinetics.

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, both after oral intake and intravenous administration.

Distribution. Plasma protein binding of pantoprazole is approximately 98%. 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 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 (about 80%), the remainder in faeces. 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.

Slow metabolizers. Approximately 3% of Europeans have low functional activity of the CYP2C19 enzyme; they are called poor metabolizers. In these individuals, pantoprazole metabolism is likely primarily catalyzed by CYP3A4. 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). The mean peak plasma concentration increased by about 60%. These results do not affect pantoprazole dosing.

Renal impairment. No dosage recommendations for dose reduction in patients with impaired renal function (including dialysis patients) are required. As in healthy volunteers, the elimination half-life of pantoprazole in these patients is short. Only very small amounts of pantoprazole are dialyzed. Despite the moderately prolonged half-life of the main metabolite (2–3 hours), elimination remains rapid, so 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, the maximum serum concentration increases only slightly – by 1.5 times – compared to healthy volunteers.

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

Children. After 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 data obtained in adult studies.

Clinical characteristics.

Indications.

Controloc® is indicated for use in adults for:

• reflux esophagitis,
• gastric and duodenal ulcers,
• 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 hydrochloric acid secretion, pantoprazole may affect the absorption of drugs for which gastric pH is an important factor for 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 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 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 PPIs concomitantly with warfarin or phenprocoumon. Increased INR and prolonged prothrombin time may lead to pathological bleeding and even death. Monitoring of INR and prothrombin time is required when these drugs are used concomitantly.

Methotrexate. Concurrent use of high-dose methotrexate (e.g., 300 mg) and proton pump inhibitors has been reported to increase methotrexate blood levels in some patients. Patients receiving high-dose methotrexate, such as those with cancer or psoriasis, should 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 via CYP3A4. Studies with drugs also metabolized via these pathways, such as carbamazepine, diazepam, glibenclamide, nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol, did not reveal clinically significant interactions.

Interaction of pantoprazole with other drugs metabolized via the same enzyme system cannot be excluded.

Results of numerous interaction studies 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), nor does it affect P-glycoprotein associated with digoxin absorption.

No interaction with concomitantly administered antacids was observed.

Interactions between pantoprazole and concomitantly administered certain antibiotics (clarithromycin, metronidazole, amoxicillin) have also been studied. No clinically significant interactions between these drugs were observed.

Drugs that inhibit or induce CYP2C19. CYP2C19 inhibitors, such as fluvoxamine, may increase the systemic effect of pantoprazole. Consideration should be given to dose reduction for patients on 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 warnings and precautions for use.

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

If symptoms persist despite adequate treatment, further investigation is required.

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

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 forms of interaction").

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.

Sodium. The medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e., is essentially sodium-free.

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

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

Bone fractures. Long-term (more than 1 year) high-dose PPI treatment 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 PPI use may increase the 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 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 carefully monitored for their development. If signs or symptoms indicating these reactions appear, pantoprazole should be discontinued immediately 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 develop, especially in sun-exposed areas, accompanied by arthralgia, the patient should seek immediate medical attention, and discontinuation of Controloc® should be considered. Development of subacute cutaneous lupus erythematosus during prior PPI therapy may increase the risk of its recurrence with other PPIs.

Effect on laboratory test results.

Elevated chromogranin A (CgA) levels may affect diagnostic test results for neuroendocrine tumours. To avoid this effect, Controloc® treatment should be temporarily discontinued at least 5 days before CgA level assessment (see section "Pharmacodynamics"). If CgA and gastrin levels do not return to normal range after initial measurement, repeat measurements should be performed 14 days after discontinuation of PPIs.

Use during pregnancy or breastfeeding.

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

Breastfeeding. Animal studies showed excretion of pantoprazole in breast milk. Data on excretion of pantoprazole in human breast milk are limited, but such excretion has been reported. Risk to newborns/infants cannot be excluded. The decision to discontinue breastfeeding or discontinue/abstain from Controloc® treatment should be made considering the benefit of breastfeeding for the child and the benefit of Controloc® treatment 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 a negligible 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.

The medicinal product should be used as prescribed and under appropriate medical supervision.

Intravenous administration of the medicinal product is recommended only when oral administration is not possible. Data are available on intravenous treatment duration up to 7 days. Therefore, as soon as oral administration of pantoprazole becomes feasible, transition from intravenous administration of Controloc® to oral pantoprazole at a dose of 40 mg should be made.

Reflux esophagitis, duodenal ulcer, gastric ulcer.

The recommended dose is 40 mg pantoprazole (1 vial) daily intravenously.

Treatment of Zollinger-Ellison syndrome and other hypersecretory conditions.

For long-term treatment of Zollinger-Ellison syndrome and other hypersecretory conditions, the recommended initial dose of Controloc® is 80 mg daily. If necessary, the dose may be titrated up or down depending on gastric acid secretion parameters. Doses exceeding 80 mg daily should be divided into two administrations. Temporary increase of pantoprazole dose to more than 160 mg may be possible, but duration of use should be limited only to the period necessary for adequate acid secretion control.

If rapid acid reduction is required, an initial dose of 2 × 80 mg is sufficient for most patients to achieve the desired level (< 10 mEq/h) within 1 hour.

Preparation for use.

Dissolve the powder in 10 mL of 0.9% sodium chloride solution provided in the vial. The solution may be administered directly or after mixing with 100 mL of 0.9% sodium chloride solution or 5% glucose solution in plastic or glass bottles.

After dilution, chemical and physical stability of the medicinal product is maintained for 12 hours at 25°C. From a microbiological standpoint, the diluted product should be used immediately.

Controloc® must not be prepared or mixed with solvents other than those specified above.

Intravenous administration should be performed over 2–15 minutes.

The vial is for single use only. Any unused medicinal product or medicinal product with changed physicochemical properties (e.g., colour change, precipitation) must be disposed of according to local regulations.

The diluted solution should be clear and yellowish.

Hepatic impairment. Patients with severe hepatic impairment should not exceed a daily dose of 20 mg (½ vial of Controloc®, powder for solution for injection 40 mg) (see section "Special warnings and precautions for use").

Renal impairment. Patients with impaired renal function do not require dose adjustment.

Elderly patients do not require dose adjustment.

Children. Controloc®, powder for solution for injection, is not recommended for use in children (under 18 years of age) due to limited data on safety and efficacy in this age group. Current data are described in the "Pharmacokinetics" section, but dosage recommendations cannot be provided.

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 a drug that is easily dialyzed.

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

Adverse reactions.

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

Adverse effects are classified by frequency as follows: 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), unknown (frequency cannot be estimated from available data).

For all adverse reactions reported during the post-marketing period, frequency cannot be determined; therefore, they are listed as "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: hyperlipidaemia and increased lipid levels (triglycerides, cholesterol), weight changes.

Unknown: hyponatraemia, hypomagnesaemia (see section "Special warnings and precautions for use"), hypocalcaemia¹, hypokalaemia¹.

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 including exacerbation of pre-existing symptoms).

Nervous system disorders.

Uncommon: headache, dizziness.

Rare: taste disturbances.

Unknown: paraesthesia.

Eye disorders.

Rare: visual disturbances/blurred vision.

Gastrointestinal disorders.

Common: fundic gland polyps (benign).

Uncommon: diarrhoea, nausea, vomiting, flatulence, constipation, dry mouth, abdominal pain and discomfort.

Unknown: microscopic colitis.

Hepatobiliary disorders.

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

Rare: increased bilirubin levels.

Unknown: hepatocellular injury, jaundice, hepatocellular failure.

Skin and subcutaneous tissue disorders.

Uncommon: skin rashes, exanthema, pruritus.

Rare: urticaria, angioneurotic oedema.

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

Musculoskeletal and connective tissue disorders.

Uncommon: hip, wrist, spine fractures (see section "Special warnings and 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: gynaecomastia.

General disorders.

Common: thrombophlebitis at injection site.

Uncommon: asthenia, fatigue, malaise.

Rare: increased body temperature, peripheral oedema.

¹ Hypocalcaemia and/or hypokalaemia may be associated with hypomagnesaemia (see section "Special warnings and precautions for use").

² Muscle spasms as a consequence of electrolyte imbalance.

Reporting of suspected adverse reactions

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

Shelf life. 2 years.

From a microbiological standpoint, the diluted product should be used immediately. However, chemical and physical stability of the diluted product is maintained for 12 hours at 25°C.

Storage conditions. Store at temperatures not exceeding 25°C in the original packaging. Keep out of reach of children!

Packaging. Powder for solution for injection in vial. 1 vial per cardboard box.

Prescription status. Prescription only.

Manufacturer. Takeda GmbH, Germany / Takeda GmbH, Germany.

Manufacturer's address. Robert-Bosch-Strasse 8, 78224 Singen, Germany / Robert-Bosch-Strasse 8, 78224 Singen, Germany.