INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KONTRACID (CONTRACID)

Composition:

Active substance: pantoprazole;

1 vial contains pantoprazole (as pantoprazole sodium) 40 mg;

Excipients: sodium hydroxide, water for injections.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: powder or loose mass of white or almost white color.

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 enzyme H⁺-K⁺-ATPase, thus blocking the final step of gastric hydrochloric acid production. The inhibition is dose-dependent and suppresses 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 (PPIs) 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 the enzyme distal to the cellular receptor, it can inhibit gastric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same following oral or intravenous administration.

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

Based on animal study results, the influence of long-term (more than 1 year) pantoprazole treatment on thyroid gland endocrine parameters cannot be completely excluded.

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Additionally, due to decreased gastric acidity, chromogranin A (CgA) levels increase. Elevated CgA levels may affect test results when diagnosing neuroendocrine tumors. 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 the normal range.

Pharmacokinetics.

Pharmacokinetic properties do not change after single or repeated administration. Within the dose range of 10 to 80 mg, the plasma pharmacokinetics of pantoprazole remain linear, both after oral administration and intravenous infusion.

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

Biological transformation. 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 half-life does not correlate with the much longer duration of action (acid secretion inhibition).

The majority of pantoprazole metabolites are excreted in the urine (approximately 80%), with the remainder eliminated in feces. The main metabolite in both plasma and urine is desmethylpantoprazole sulfate conjugate. The half-life of the main metabolite (about 1.5 hours) is only slightly longer than that of pantoprazole.

Special patient groups.

Slow metabolizers. Approximately 3% of Europeans have low functional activity of the enzyme CYP2C19 and are referred to as slow metabolizers. In these individuals, pantoprazole metabolism is likely catalyzed primarily by the CYP3A4 enzyme. After a single 40 mg dose of pantoprazole, the mean area under the plasma concentration-time curve (AUC) was approximately 6 times higher in slow metabolizers than in individuals with functionally active CYP2C19 (fast metabolizers). The mean maximum plasma concentration increased by approximately 60%. These findings do not affect pantoprazole dosing.

Renal impairment. No dosage reduction recommendations are required when administering pantoprazole to patients with impaired renal function (including patients on dialysis). As in healthy volunteers, the half-life of pantoprazole is 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 half-life of pantoprazole increases to 7–9 hours and AUC increases 5–7 times, the maximum serum concentration (C_max) increases only slightly (by 1.5 times) compared to healthy volunteers.

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

Children. After a single intravenous dose of pantoprazole at 0.8 or 1.6 mg/kg in children aged 2 to 16 years, no significant correlation was observed between pantoprazole clearance and patient age or body weight. AUC and volume of distribution corresponded to data obtained in adult studies.

Clinical characteristics.

Indications.

Contacid is indicated for use in adults for:

gastroesophageal reflux disease (GERD),
gastric and duodenal ulcers,
Zollinger-Ellison syndrome and other hypersecretory conditions.

Contraindications.

Hypersensitivity to the active substance, benzimidazole derivatives, or to 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 PPIs 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 does not affect the pharmacokinetics of warfarin, phenprocoumon, or INR (International Normalized Ratio). However, there have been reports of increased INR and prolonged prothrombin time in patients receiving concomitant PPIs and warfarin or phenprocumon. Elevated INR and prolonged prothrombin time may lead to the development of pathological bleeding and even fatal outcomes. Monitoring of INR and prothrombin time is required when these drugs are used concomitantly.

Methotrexate. Concomitant administration of high doses of methotrexate (e.g., 300 mg) and PPIs increases blood methotrexate levels in some patients. Patients receiving high-dose methotrexate therapy, 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 by CYP2C19; other metabolic pathways include oxidation by CYP3A4. Studies with drugs that are also metabolized via these pathways—such as carbamazepine, diazepam, glyburide (glibenclamide), nifedipine, and oral contraceptives containing levonorgestrel and ethinylestradiol—have not revealed clinically significant interactions.

Interaction between pantoprazole and other drugs metabolized by the same enzyme system cannot be ruled out.

Results from several studies on potential interactions indicate that pantoprazole does not affect the metabolism of 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 certain concomitantly administered antibiotics (clarithromycin, metronidazole, amoxicillin) have also been conducted. No clinically significant interactions were observed between these drugs.

Medicinal products that inhibit or induce CYP2C19. Inhibitors of CYP2C19, such as fluvoxamine, may increase the systemic exposure to pantoprazole. Consideration should be given to reducing the dose in patients receiving long-term, high-dose pantoprazole therapy and in 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 (THC) have been reported in patients taking pantoprazole. Alternative confirmatory testing methods should be considered to verify positive results.

Special precautions for use.

Malignant gastric neoplasms. 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), as well as in suspected or confirmed gastric ulcer, malignancy must be excluded.

If symptoms persist despite adequate treatment, additional investigations are required.

Hepatic impairment. Patients with severe hepatic impairment require regular monitoring of liver enzymes. If liver enzymes increase, treatment with the drug 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 a significant reduction in their bioavailability (see section "Interaction with other medicinal products and other forms of interaction").

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

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

Hypomagnesemia. Cases of severe hypomagnesemia have been reported in patients treated with PPIs, such as pantoprazole, for at least 3 months, and in most cases for over 1 year. Serious clinical manifestations of hypomagnesemia, such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, may occur and initially develop insidiously. Hypomagnesemia may lead to the development of hypocalcemia and/or hypokalemia (see section "Undesirable effects"). In cases of hypomagnesemia (and hypocalcemia and/or hypokalemia associated with hypomagnesemia), the condition of patients improved in most cases after replacement therapy with magnesium supplements and after discontinuation of PPI treatment.

Patients requiring long-term therapy or those receiving PPIs concomitantly with digoxin or medications that may cause hypomagnesemia (e.g., diuretics) should have their magnesium levels measured before initiating PPI treatment and periodically during treatment.

Bone fractures. Long-term treatment (more than 1 year) with high doses of PPIs may moderately increase the risk of hip, wrist, and spine fractures, primarily in elderly patients or in the presence of other risk factors.

Observational studies indicate that PPI use may increase the overall risk of fractures 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 consume adequate amounts of vitamin D and calcium.

Severe cutaneous adverse reactions. Serious cutaneous adverse reactions associated with pantoprazole use, with unknown frequency (see section "Undesirable effects"), 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 the signs and symptoms of these skin reactions, and should be closely monitored for their development. If signs or symptoms suggestive of these reactions occur, pantoprazole should be discontinued immediately and alternative treatment considered.

Subacute cutaneous lupus erythematosus. The use of PPIs 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 Contacid should be considered. Previous occurrence of subacute cutaneous lupus erythematosus during prior PPI therapy may increase the risk of recurrence with other PPIs.

Effect on laboratory test results. Elevated chromogranin A (CgA) levels may interfere with diagnostic tests for neuroendocrine tumors. To avoid this interference, treatment with Contacid should be temporarily discontinued at least 5 days before assessment of CgA levels (see section "Pharmacodynamics"). If CgA and gastrin levels have not returned to normal range after initial measurement, repeat measurements should be performed 14 days after discontinuation of PPI treatment.

Use during pregnancy or breastfeeding.

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

Breastfeeding period. Animal studies have shown excretion of pantoprazole into breast milk. There is insufficient data on the excretion of pantoprazole into human breast milk, although such excretion has been reported. Risk to the newborn/infant cannot be excluded. The decision to discontinue breastfeeding or to discontinue/abstain from treatment with Contacid should be made taking into account the benefits of breastfeeding for the child and the benefits of treatment with Contacid for the woman.

Fertility. Pantoprazole did not impair fertility in animal studies.

Ability to influence the speed of reactions while driving or operating machinery.

Pantoprazole has no effect or has a negligible effect on the ability to drive or operate machinery. The possible occurrence of adverse reactions such as dizziness and visual disturbances should be taken into account (see section "Undesirable effects"). In such cases, driving or operating machinery should be avoided.

Method of Administration and Dosage

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

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

Gastroesophageal reflux disease, duodenal ulcer, gastric ulcer.

The recommended dose is 40 mg of pantoprazole (1 vial) once 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 Contacid is 80 mg daily. The dose may be titrated up or down as necessary, depending on gastric acid secretion parameters. Doses exceeding 80 mg daily should be divided into two administrations. A temporary increase in pantoprazole dose to more than 160 mg may be possible; however, the duration of use should be limited only to the period required for adequate control of acid secretion.

If rapid reduction of acidity 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. The powder should be dissolved 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 infusion bottles.

After reconstitution, the chemical and physical stability of the medicinal product is maintained for 12 hours at 25 °C. From a microbiological standpoint, the diluted solution should be used immediately. Contacid 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 intended for single use only. Any unused portion or product with altered physicochemical properties (e.g. color change, precipitation) must be discarded according to local regulations.

The reconstituted solution should be clear and yellowish.

Hepatic impairment. In patients with severe hepatic dysfunction, the daily dose should not exceed 20 mg (½ vial of Contacid, powder for solution for injection 40 mg) (see section "Special precautions").

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

Elderly patients. Dose adjustment is not required.

Children.

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

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 should be administered. There are no recommendations for specific antidotal therapy.

Side effects

Adverse reactions may be expected in approximately 5% 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), frequency not known (frequency cannot be estimated from the available data).

For all adverse reactions reported during the post-marketing period, it is not possible to determine the frequency; therefore, they are listed as having a frequency of "frequency 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;
Frequency not known – hyponatremia, hypomagnesemia (see section "Special precautions for use"), hypocalcemia\textsuperscript{1}, hypokalemia\textsuperscript{1}.

Psychiatric disorders:
Uncommon – sleep disorders;
Rare – depression (including exacerbation);
Very rare – confusion (including exacerbation);
Frequency not known – hallucinations, confusion (particularly in patients predisposed to such disorders, as well as exacerbation of these symptoms if previously present).

Nervous system disorders:
Uncommon – headache, dizziness;
Rare – taste disturbances;
Frequency not known – paraesthesia.

Eye disorders:
Rare – visual disturbances/blurred vision.

Gastrointestinal disorders:
Common – fundic gland polyps (benign);
Uncommon – diarrhea, nausea, vomiting, flatulence, constipation, dry mouth, abdominal pain and discomfort;
Frequency not known – microscopic colitis.

Hepatobiliary disorders:
Uncommon – increased liver enzymes (transaminases, γ-GT);
Rare – increased bilirubin levels;
Frequency not known – hepatocellular injury, jaundice, hepatocellular failure.

Skin and subcutaneous tissue disorders:
Uncommon – skin rashes, exanthema, pruritus;
Rare – urticaria, angioneurotic edema;
Frequency not known – Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special precautions for use"), drug reaction with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal and connective tissue disorders:
Uncommon – fractures of the femur, wrist, spine (see section "Special precautions for use");
Rare – arthralgia, myalgia;
Frequency not known – muscle spasms\textsuperscript{2}.

Renal and urinary disorders:
Frequency not known – tubulointerstitial nephritis (with possible development of renal failure).

Reproductive system and breast disorders:
Rare – gynecomastia.

General disorders:
Common – phlebitis at the injection site;
Uncommon – asthenia, fatigue, malaise;
Rare – increased body temperature, peripheral edema.

\textsuperscript{1} Hypocalcemia and/or hypokalemia may be associated with the development of hypomagnesemia (see section "Special precautions for use").
\textsuperscript{2} Muscle spasms as a result of electrolyte imbalance.

Reporting of suspected adverse reactions. Reporting of suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

From a microbiological standpoint, the reconstituted preparation should be used immediately. However, the physicochemical stability of the reconstituted preparation is maintained for 12 hours at 25 °C.

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

Packaging. Powder for solution for injection, 40 mg in a vial. 1, 5, or 10 vials per pack.

Prescription status. Prescription only.

Manufacturer. Private Joint-Stock Company "Lekhim-Kharkiv".

Production of bulk product by Reyoung Pharmaceutical Co., Ltd., People's Republic of China.

Manufacturer's address and location of business activity.
36 Severina Pototskoho Street, Kharkiv, Kharkiv Oblast, 61115, Ukraine.

Contracid