Reflyupant

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT REFLUPANT (REFLUPANT)

Composition:

Active substance: pantoprazole;

1 vial contains 40.0 mg of pantoprazole (as pantoprazole sodium sesquihydrate);

Excipients: edetate disodium, sodium hydroxide.

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical properties: porous mass or powder, white or almost white.

Pharmacotherapeutic group.

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

Pharmacological Properties

Pharmacodynamics. 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 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 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 gastric acid secretion regardless 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 in most cases do not exceed the upper limit of normal. With long-term treatment, levels typically increase approximately twofold. Marked elevation occurs only in isolated cases. As a result, prolonged therapy may occasionally lead to mild or moderate increase in gastric enterochromaffin-like (ECL) cells (similar to adenomatoid hyperplasia). However, according to available studies, the development of neuroendocrine tumor precursor cells (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 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 rise. Elevated CgA levels may interfere with diagnostic testing for 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 therapy, to return to the normal range.

Pharmacokinetics.

Pharmacokinetic properties remain unchanged after single or repeated administration. Within the dose range of 10 to 80 mg, the plasma pharmacokinetics of pantoprazole are linear, both after oral administration and intravenous infusion.

Distribution. Plasma protein binding of pantoprazole is approximately 98%. The volume of distribution is about 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 about 0.1 L/h/kg. A few 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%), with the remainder eliminated in feces. 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 enzyme CYP2C19; these individuals are referred to as poor metabolizers. In such individuals, pantoprazole metabolism is likely primarily catalyzed by CYP3A4. After a single 40 mg dose of pantoprazole, the mean area under the plasma concentration-time curve (AUC) was approximately 6 times higher in poor metabolizers than in individuals with functionally active CYP2C19 (extensive metabolizers). The mean peak plasma concentration increased by approximately 60%. These findings do not affect pantoprazole dosing.

Renal impairment. No dose adjustment recommendations are necessary when prescribing 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. 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 observed 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 was observed between pantoprazole clearance and patient age or body weight. AUC and volume of distribution were consistent with data obtained in adult studies.

Clinical characteristics.

Indications.

Reflupant is indicated for use in adults for:

• gastroesophageal reflux disease;
• 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 interactions.

Medicinal products whose absorption depends on pH. Due to complete and prolonged inhibition of hydrochloric acid secretion, pantoprazole may affect the absorption of drugs for which gastric juice pH is an important factor of their bioavailability (e.g., certain antifungal agents such as ketoconazole, itraconazole, posaconazole, or other drugs such as erlotinib).

HIV protease inhibitors. Concomitant use of proton pump inhibitors with HIV protease inhibitors whose absorption depends on intragastric pH (such as atazanavir) 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 use of pantoprazole with warfarin or phenprocoumon did 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 phenprocoumon. Increased INR and prolonged prothrombin time may lead to pathological bleeding and even death. Monitoring of INR and prothrombin time is necessary when these drugs are used concomitantly.

Methotrexate. It has been reported 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 doses of methotrexate, such as those with cancer or psoriasis, should temporarily discontinue pantoprazole therapy.

Other interactions. Pantoprazole is mainly 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.

Interactions between pantoprazole and other drugs metabolized by the same enzyme system cannot be excluded.

Results from numerous 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), CYP2E1 (e.g., ethanol), or affect P-glycoprotein-mediated digoxin absorption.

No interaction was observed with concomitantly administered antacids.

Interaction studies between pantoprazole and certain antibiotics used concomitantly (clarithromycin, metronidazole, amoxicillin) have also 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. 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 with laboratory tests. There have been reports of false-positive results in certain urine screening tests for tetrahydrocannabinol (THC) in patients receiving pantoprazole. Alternative testing methods should be considered to confirm positive results.

Special precautions for use.

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

If symptoms persist despite adequate treatment, further 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 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 interactions").

Gastrointestinal infections caused by bacteria. Treatment with pantoprazole 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., essentially a sodium-free preparation.

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, for over a year. Serious clinical manifestations of hypomagnesemia, such as fatigue, tetany, delirium, seizures, dizziness, and ventricular arrhythmia, may occur and initially develop insidiously. Hypomagnesemia may lead to the development of hypocalcemia and/or hypokalemia (see section "Adverse reactions"). In most cases, the condition of patients with hypomagnesemia and associated hypocalcemia and/or hypokalemia improved after corrective therapy with magnesium supplements and 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 assessed before initiating PPI treatment and periodically during treatment.

Bone fractures. Long-term treatment (more than 1 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 in the presence of other risk factors.

Observational studies indicate that the use of proton pump inhibitors may increase the overall risk of fractures by 10–40%. Some of these 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 (SCAR). Cases of severe cutaneous adverse reactions (SCARs) have been reported with pantoprazole, including erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which may be life-threatening or even fatal (see section "Adverse reactions"). The frequency of these reactions is unknown.

When prescribing pantoprazole, patients should be informed about the signs and symptoms of such reactions, and skin condition should be carefully monitored. If signs or symptoms indicating severe skin reactions occur, treatment with pantoprazole should be discontinued immediately and alternative therapy considered.

Subacute cutaneous lupus erythematosus. The use of proton pump inhibitors has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions develop, particularly in areas exposed to sunlight, and are accompanied by arthralgia, the patient should seek immediate medical advice, and discontinuation of Reflupant should be considered. Development of subacute cutaneous lupus erythematosus in patients during prior treatment with proton pump inhibitors may increase the risk of its recurrence when using other proton pump inhibitors.

Effect on laboratory test results. Elevated chromogranin A (CgA) levels may interfere with diagnostic tests for neuroendocrine tumors. To avoid such interference, treatment with Reflupant should be temporarily discontinued at least 5 days before assessing CgA levels (see section "Pharmacodynamics"). If CgA and gastrin levels do not return to the normal range 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 pantoprazole in pregnant women (approximately 300–1000 pregnancy outcomes reported) indicate no malformative or fetal/neonatal toxicity of the drug. Reproductive toxicity was observed in animal studies. As a precautionary measure, use of Reflupant in pregnant women should be avoided.

Breastfeeding. Animal studies have shown excretion of pantoprazole into breast milk. Data on excretion of pantoprazole into human breast milk are limited, but such excretion has been reported. Risk to newborns/infants cannot be excluded. The decision to discontinue breastfeeding or to discontinue/abstain from treatment with Reflupant should be made taking into account the benefit of breastfeeding for the child and the benefit of treatment with Reflupant for the woman.

Fertility. Pantoprazole did not impair fertility in animal studies.

Ability to affect reaction speed while driving or operating machinery.

Pantoprazole has no effect or a negligible effect on the ability to drive or operate machinery. The possible development 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

The drug 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, intravenous administration of Reflupant should be discontinued and oral administration initiated at a dose of 40 mg.

Gastroesophageal reflux disease, duodenal ulcer, gastric ulcer.

The recommended dose is 40 mg of pantoprazole (1 vial) per day administered 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 Reflupant is 80 mg per day. If necessary, the dose may be titrated, either increased or decreased, depending on gastric acid secretion parameters. Doses exceeding 80 mg per day should be divided into two administrations. Temporary dose increases above 160 mg may be considered, but treatment duration should be limited to the period required for adequate control of acid secretion.

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.

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 bags.

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

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

Intravenous administration of the drug should be performed over 2–15 minutes.

The vial is intended for single use only. Any unused portion or drug with altered physicochemical properties (e.g. color change, precipitation) must be discarded according to local regulations.

The reconstituted solution should be clear and yellowish in color.

Hepatic impairment. In patients with severe hepatic impairment, the daily dose should not exceed 20 mg (½ vial of Reflupant) (see section "Special Warnings and Precautions").

Renal impairment. Dose adjustment is not required in patients with renal impairment.

Elderly patients do not require dose adjustment.

Children.

Reflupant 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 available data are described in the section "Pharmacokinetics"; however, 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 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 may be expected in approximately 5% of patients. The most common adverse reaction is thrombophlebitis at the injection site. Diarrhea and headache occurred in about 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 (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), and not known (frequency cannot be estimated from available data).

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"), hypocalcemia¹, hypokalemia¹

Psychiatric disorders

Uncommon: sleep disorders
Rare: depression (including exacerbation)
Very rare: confusion (including exacerbation)
Not known: hallucinations, confusion (especially in patients predisposed to such disorders, and exacerbation of these symptoms if previously present)

Nervous system disorders

Uncommon: headache, dizziness
Rare: taste disturbances
Not known: paresthesia

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
Not known: microscopic colitis

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, Lyell’s syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), erythema multiforme, photosensitivity, subacute cutaneous lupus erythematosus (see section "Special precautions for use")

Musculoskeletal and connective tissue disorders

Uncommon: fractures of the femur, wrist, spine (see section "Special precautions for use")
Rare: arthralgia, myalgia
Not known: muscle spasms²

Renal and urinary disorders

Not known: interstitial nephritis (with possible development of renal failure)

Reproductive system and breast disorders

Rare: gynecomastia

General disorders

Common: thrombophlebitis at the injection site
Uncommon: asthenia, fatigue, malaise
Rare: increased body temperature, peripheral edema

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

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

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

Storage conditions

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

Incompatibilities

This medicinal product must not be mixed with other medicinal products except those specified in the section "Administration and dosage".

Packaging

Lyophilisate for solution for injection in a vial. 1 vial per carton.

Prescription status. Prescription only.

Manufacturer

Public Joint-Stock Company "Scientific and Production Center "Boryspil Chemical-Pharmaceutical Plant".

Manufacturer's address and place of business

17 Myru Street, Kyiv, 03134, Ukraine