Rabiet^® (Capsules) Instructions for Use

ATC Code

A02BC04 (Rabeprazole)

Active Substance

Rabeprazole (Rec.INN registered by WHO)

Clinical-Pharmacological Group

H⁺-K⁺-ATPase inhibitor. Antiulcer drug

Pharmacotherapeutic Group

Gastric secretion reducing agent – proton pump inhibitor

Pharmacological Action

H⁺-K⁺-ATPase inhibitor. Antiulcer drug.

Mechanism of action

Rabeprazole sodium belongs to the class of antisecretory compounds, substituted benzimidazoles.

Rabeprazole sodium suppresses gastric acid secretion by specific inhibition of H⁺/K⁺ ATPase at the secretory surface of the gastric parietal cell.

H⁺/K⁺ ATPase is a protein complex that functions as a proton pump, thus Rabeprazole sodium is a gastric proton pump inhibitor and blocks the final stage of acid production.

This effect is dose-dependent and leads to inhibition of both basal and stimulated acid secretion, regardless of the stimulus.

Rabeprazole sodium does not have anticholinergic properties.

Antisecretory effect

After oral administration of rabeprazole sodium at a dose of 20 mg, the antisecretory effect develops within 1 hour.

Inhibition of basal and stimulated acid secretion 23 hours after the first dose of rabeprazole sodium is 69% and 82%, respectively, and lasts up to 48 hours.

This duration of pharmacodynamic action far exceeds the predictable T_1/2 (approximately 1 hour).

This effect can be explained by the prolonged binding of the drug to the H⁺/K⁺ ATPase of gastric parietal cells.

The magnitude of the inhibitory effect of rabeprazole sodium on acid secretion reaches a plateau after 3 days of rabeprazole sodium administration.

Upon discontinuation of administration, secretory activity is restored within 1-2 days.

Effect on plasma gastrin concentration

In clinical studies, patients took Rabeprazole sodium at doses of 10 or 20 mg daily for up to 43 months.

Plasma gastrin concentration was increased for the first 2-8 weeks, reflecting the inhibitory effect on acid secretion.

Gastrin concentration usually returned to baseline within 1-2 weeks after discontinuation of treatment.

Effect on enterochromaffin-like cells

In a study of human gastric biopsy specimens from the antrum and fundus of 500 patients receiving Rabeprazole sodium or a comparator drug for 8 weeks, no persistent changes in the morphological structure of enterochromaffin-like cells, severity of gastritis, incidence of atrophic gastritis, intestinal metaplasia, or spread of Helicobacter pylori infection were found.

In a study involving more than 400 patients receiving Rabeprazole sodium (10 mg/day or 20 mg/day) for up to 1 year, the incidence of hyperplasia was low and comparable to that of omeprazole (20 mg/kg).

No cases of adenomatous changes or carcinoid tumors observed in rats were reported.

Other effects

No systemic effects of rabeprazole sodium on the CNS, cardiovascular or respiratory systems have been detected to date.

It has been shown that oral Rabeprazole sodium at a dose of 20 mg for 2 weeks does not affect thyroid function, carbohydrate metabolism, blood parathyroid hormone concentration, or the concentration of cortisol, estrogens, testosterone, prolactin, glucagon, FSH, LH, renin, aldosterone and somatotropic hormone.

Pharmacokinetics

Absorption and distribution

Rabeprazole is rapidly absorbed from the intestine, C_max in plasma is reached approximately 3.5 hours after a dose of 20 mg.

Changes in plasma C_max and AUC values of rabeprazole are linear in the dose range from 10 to 40 mg.

The absolute bioavailability after oral administration of a 20 mg dose (compared to intravenous administration) is about 52%.

In addition, bioavailability does not change with repeated administration of rabeprazole.

Neither the time of day of administration nor antacids affect the absorption of rabeprazole.

Taking the drug with fatty food slows down the absorption of rabeprazole by 4 hours or more, but neither C_max nor the degree of absorption changes.

The binding of rabeprazole to plasma proteins is about 97%.

Metabolism

The main metabolite is the thioether (M1).

The only active metabolite is desmethyl (M3), but it was detected at low concentration in only one study participant after taking rabeprazole at a dose of 80 mg.

After a single dose of ¹⁴C-labeled rabeprazole sodium at a dose of 20 mg, no unchanged drug was found in the urine.

About 90% of rabeprazole is excreted by the kidneys mainly in the form of two metabolites: a mercapturic acid conjugate (M5) and a carboxylic acid (M6), as well as in the form of two unknown metabolites identified during toxicological analysis.

The remainder of the administered rabeprazole sodium is excreted through the intestines.

Total excretion is 99.8%.

These data indicate a small excretion of rabeprazole sodium metabolites in the bile.

In healthy volunteers, T_1/2 from plasma is about 1 hour (ranging from 0.7 to 1.5 hours), total clearance is 3.8 ml/min/kg.

Pharmacokinetics in special patient groups

In patients with chronic liver damage, AUC is doubled compared to healthy volunteers, indicating a decrease in first-pass metabolism, and T_1/2 from plasma is increased by 2-3 times.

In patients with stable end-stage renal failure requiring maintenance hemodialysis (CrCl <5 ml/min/1.73 m²), the excretion of rabeprazole sodium is similar to that in healthy volunteers.

AUC and C_max in such patients were approximately 35% lower than in healthy volunteers.

On average, T_1/2 of rabeprazole was 0.82 hours in healthy volunteers; 0.95 hours in patients during hemodialysis and 3.6 hours after hemodialysis.

Clearance of the drug in patients with kidney disease requiring hemodialysis was approximately 2 times higher than in healthy volunteers.

Patients with chronic compensated liver cirrhosis tolerate Rabeprazole sodium at a dose of 20 mg once a day, although the AUC is doubled and C_max is increased by 50% compared to healthy volunteers of the corresponding sex.

In elderly patients, the elimination of rabeprazole is somewhat slowed.

After 7 days of using rabeprazole at 20 mg/day, the AUC in elderly individuals was approximately twice as high and C_max was increased by 60% compared to young healthy volunteers.

However, no signs of rabeprazole accumulation were noted.

In patients with slow CYP2C19 metabolism, after 7 days of using rabeprazole at a dose of 20 mg/day, AUC increases by 1.9 times and T_1/2 by 1.6 times compared to the same parameters in “rapid metabolizers”, while C_max increases by 40%.

Indications

• Gastric ulcer in the acute phase and anastomotic ulcer;
• Duodenal ulcer in the acute phase;
• Erosive and ulcerative gastroesophageal reflux disease or reflux esophagitis;
• Maintenance therapy for gastroesophageal reflux disease;
• Non-erosive gastroesophageal reflux disease;
• Zollinger-Ellison syndrome and other conditions characterized by pathological hypersecretion;
• In combination with appropriate antibacterial therapy for the eradication of Helicobacter pylori in patients with peptic ulcer disease.

ICD codes

Dosage Regimen

Capsules

The drug is taken orally.

The capsules should be swallowed whole, without chewing or crushing.

It has been established that neither the time of day nor food intake affects the activity of rabeprazole sodium.

For gastric ulcer in the acute phase and anastomotic ulcer, it is recommended to take 20 mg once a day.

Healing usually occurs after 6 weeks of therapy, but in some cases, the duration of treatment may be extended for another 6 weeks.

For duodenal ulcer in the acute phase, it is recommended to take 20 mg once a day.

The duration of treatment is from 2 to 4 weeks.

If necessary, the duration of treatment can be extended for another 4 weeks.

For treatment of erosive gastroesophageal reflux disease or reflux esophagitis, it is recommended to take 20 mg once a day.

The duration of treatment is from 4 to 8 weeks.

If necessary, the duration of treatment can be extended for another 8 weeks.

For maintenance therapy of gastroesophageal reflux disease (GERD), it is recommended to take 20 mg once a day.

The duration of treatment depends on the patient’s condition.

For non-erosive gastroesophageal reflux disease (NERD) without esophagitis, it is recommended to take 20 mg once a day.

If symptoms do not disappear after 4 weeks of treatment, the patient should be further examined.

After symptom relief, to prevent their subsequent occurrence, the drug should be taken orally once a day as needed.

For treatment of Zollinger-Ellison syndrome and other conditions characterized by pathological hypersecretion, the dose is selected individually.

The initial dose is 60 mg/day, then the dose is increased and the drug is prescribed at a dose of up to 100 mg/day in a single dose or 60 mg twice a day.

For some patients, divided dosing of the drug is preferable.

Treatment should be continued as clinically necessary.

In some patients with Zollinger-Ellison syndrome, the duration of treatment with rabeprazole was up to 1 year.

For Helicobacter pylori eradication, it is recommended to take 20 mg twice a day according to a specific regimen with an appropriate combination of antibiotics.

The duration of treatment is 7 days.

Dose adjustment in patients with renal insufficiency is not required.

In patients with mild to moderate hepatic impairment, the concentration of rabeprazole in the blood is usually higher than in healthy patients.

Caution should be exercised when prescribing the drug Rabiet^® to patients with severe hepatic impairment.

Dose adjustment in elderly patients is not required.

The safety and efficacy of rabeprazole sodium 20 mg for short-term (up to 8 weeks) treatment of GERD in children aged 12 years and older is confirmed by extrapolation of the results of adequate and well-controlled studies supporting the efficacy of rabeprazole sodium for adults and safety and pharmacokinetic studies for pediatric patients.

The recommended dose for children aged 12 years and older is 20 mg once a day for up to 8 weeks.

The safety and efficacy of rabeprazole sodium for treatment of GERD in children under 12 years of age has not been established.

The safety and efficacy of rabeprazole sodium for use in other indications has not been established for pediatric patients.

Adverse Reactions

Based on the experience of clinical studies, it can be concluded that Rabeprazole is usually well tolerated by patients.

Side effects are generally mild or moderate and transient.

When using rabeprazole in clinical studies, the following side effects were noted.

From the nervous system headache, dizziness.

From the digestive system abdominal pain, diarrhea, flatulence, constipation, dry mouth.

Other rash, peripheral edema.

During post-registration use of the drug, the following side effects have been reported.

From the digestive system increased activity of liver enzymes; rarely – hepatitis, jaundice.

In patients with liver cirrhosis, the development of hepatic encephalopathy has rarely been reported.

From the hematopoietic system rarely – thrombocytopenia, neutropenia, leukopenia.

From the musculoskeletal system rarely – myalgia, arthralgia.

Allergic reactions rarely – bullous eruptions, urticaria, acute systemic allergic reactions; very rarely – erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Other rarely – hypomagnesemia; very rarely – development of interstitial nephritis, gynecomastia.

No changes in other laboratory parameters were observed during the administration of rabeprazole sodium.

According to post-marketing surveillance data, when taking proton pump inhibitors, an increased risk of fractures may occur.

Contraindications

• Sucrase/isomaltase deficiency, fructose intolerance, glucose-galactose malabsorption syndrome;
• Pregnancy;
• Breastfeeding period;
• Age under 12 years;
• Hypersensitivity to rabeprazole, substituted benzimidazoles or to the auxiliary components of the drug.

With caution the drug should be prescribed in childhood, in severe renal failure.

Use in Pregnancy and Lactation

There are no data on the safety of rabeprazole use during pregnancy.

Reproductive studies in rats and rabbits revealed no signs of impaired fertility or fetal developmental defects due to rabeprazole; however, in rats, the drug penetrates the placental barrier in small amounts.

The drug Rabiet^® should not be used during pregnancy except in cases where the expected positive effect for the mother outweighs the possible risk to the fetus.

It is not known whether Rabeprazole is excreted in breast milk.

Appropriate studies in women during breastfeeding have not been conducted.

However, Rabeprazole has been found in the milk of lactating rats, so the drug Rabiet^® should not be prescribed to women during breastfeeding.

Use in Hepatic Impairment

Caution is recommended when first prescribing Rabeprazole to patients with severe liver dysfunction.

Use in Renal Impairment

The drug should be prescribed with caution to patients with severe renal failure.

Pediatric Use

The use of the drug is contraindicated in children under 12 years of age.

The safety and efficacy of rabeprazole sodium 20 mg for short-term (up to 8 weeks) treatment of GERD in children aged 12 years and older is confirmed by extrapolation of the results of adequate and well-controlled studies supporting the efficacy of rabeprazole sodium for adults and safety and pharmacokinetic studies for pediatric patients.

The recommended dose for children aged 12 years and older is 20 mg once a day for up to 8 weeks.

The safety and efficacy of rabeprazole sodium for the treatment of GERD in children under 12 years of age has not been established.

The safety and efficacy of rabeprazole sodium for use in other indications has not been established for pediatric patients.

Geriatric Use

No dose adjustment is required in elderly patients.

Special Precautions

The patient’s response to therapy with rabeprazole sodium does not exclude the presence of malignant neoplasms in the stomach.

In a special study in patients with mild or moderate liver dysfunction, no significant difference in the frequency of side effects of rabeprazole from that in sex- and age-matched healthy individuals was found, but despite this, caution is recommended when first prescribing Rabeprazole to patients with severe liver dysfunction.

No dose adjustment of rabeprazole is required for patients with renal or hepatic impairment.

The AUC of rabeprazole sodium in patients with severe hepatic impairment is approximately 2 times higher than in healthy patients.

Hypomagnesemia

During treatment with proton pump inhibitors for at least 3 months, rare cases of symptomatic or asymptomatic hypomagnesemia have been noted.

In most cases, these reports were received after one year of therapy.

Serious adverse events were tetany, arrhythmia, convulsions.

Most patients required treatment for hypomagnesemia, including magnesium replacement and discontinuation of proton pump inhibitors.

In patients who will receive long-term treatment, or are taking proton pump inhibitors with drugs such as digoxin, or drugs that can cause hypomagnesemia (e.g., diuretics), magnesium concentration should be monitored before starting treatment with proton pump inhibitors and during treatment.

Other acid-reducing agents, such as histamine H₂-receptor blockers or proton pump inhibitors, should not be taken simultaneously with the drug Rabiet^®.

Bone fractures

According to observational studies, it can be assumed that therapy with proton pump inhibitors may lead to an increased risk of osteoporosis-related fractures of the hip, wrist, or spine.

The risk of fractures was increased in patients who received proton pump inhibitors in high doses for a long time (a year or more).

High doses should be understood as doses exceeding those recommended in the instructions.

Concomitant use with methotrexate

According to literature data, concomitant use of proton pump inhibitors with methotrexate (primarily in high doses) may lead to an increase in the concentration of methotrexate and/or its metabolite hydroxymethotrexate and prolong its elimination time, which may lead to the manifestation of methotrexate toxicity.

If it is necessary to use methotrexate in high doses, the possibility of temporary discontinuation of proton pump inhibitor therapy may be considered.

Clostridium difficile

Proton pump inhibitor therapy may lead to an increased risk of gastrointestinal infections, such as infections caused by Clostridium difficile.

Effect on the Ability to Drive Vehicles and Operate Machinery

Based on the pharmacodynamic characteristics of rabeprazole and the adverse event profile, it is unlikely that the drug affects the ability to drive vehicles and operate machinery. However, if drowsiness occurs, these activities should be avoided.

Overdose

Data on intentional or accidental overdose are minimal. No cases of severe rabeprazole overdose have been reported.

Treatment symptomatic and supportive therapy should be administered. No specific antidote for rabeprazole is known. Rabeprazole is highly bound to plasma proteins and is therefore poorly dialyzable.

Drug Interactions

Cytochrome P450 System

Rabeprazole sodium, like other proton pump inhibitors, is metabolized by the cytochrome P450 (CYP450) system in the liver. In vitro studies using human liver microsomes showed that rabeprazole sodium is metabolized by the CYP2C19 and CYP3A4 isoenzymes.

Studies in healthy volunteers have shown that rabeprazole sodium has no pharmacokinetic or clinically significant interaction with drugs metabolized by the cytochrome P450 system – warfarin, phenytoin, theophylline, and diazepam (regardless of whether patients are extensive or poor metabolizers of diazepam).

A study of combination therapy with antibacterial drugs was conducted. In this four-way study, 16 healthy volunteers received 20 mg rabeprazole, 1000 mg amoxicillin, 500 mg clarithromycin, or a combination of these three drugs (RAC – Rabeprazole, Amoxicillin, Clarithromycin). The AUC and C_max values for clarithromycin and amoxicillin were similar when comparing combination therapy with monotherapy. The AUC and C_max values for rabeprazole increased by 11% and 34%, respectively, and for 14-hydroxyclarithromycin (an active metabolite of clarithromycin), the AUC and C_max increased by 42% and 46%, respectively, for combination therapy compared to monotherapy. This increase in exposure for rabeprazole and clarithromycin was not considered clinically significant.

Interaction Due to Inhibition of Gastric Acid Secretion

Rabeprazole sodium provides sustained and prolonged suppression of gastric acid secretion. Therefore, an interaction with substances whose absorption is pH-dependent may occur. When taken concomitantly with rabeprazole sodium, the absorption of ketoconazole is reduced by 30%, and the absorption of digoxin is increased by 22%. Consequently, some patients should be monitored to determine if dose adjustment is necessary when rabeprazole sodium is used concomitantly with ketoconazole, digoxin, or other drugs whose absorption is pH-dependent.

Atazanavir

When atazanavir 300 mg/ritonavir 100 mg was co-administered with omeprazole (40 mg once daily) or atazanavir 400 mg was co-administered with lansoprazole (60 mg once daily) in healthy volunteers, a significant reduction in atazanavir exposure was observed. The absorption of atazanavir is pH-dependent. Although concomitant administration with rabeprazole has not been studied, similar results are expected for other proton pump inhibitors. Therefore, the concomitant use of atazanavir with proton pump inhibitors, including Rabeprazole, is not recommended.

Antacids

In clinical studies, antacids were used concomitantly with rabeprazole sodium. No clinically significant interaction between rabeprazole sodium and aluminum hydroxide gel or magnesium hydroxide was observed.

Food Intake

In a clinical study, no clinically significant interaction was observed when rabeprazole sodium was taken with a low-fat meal. Taking rabeprazole sodium with a high-fat meal may delay the absorption of rabeprazole by up to 4 hours or more; however, C_max and AUC are not changed.

Cyclosporine

In vitro experiments using human liver microsomes showed that Rabeprazole inhibits the metabolism of cyclosporine with an IC₅₀ of 62 µmol, i.e., at a concentration 50 times greater than the C_max for healthy volunteers after 20 days of rabeprazole administration at a dose of 20 mg. The degree of inhibition is similar to that of omeprazole at equivalent concentrations.

Methotrexate

Based on adverse event reports, published pharmacokinetic studies, and retrospective analysis data, it can be assumed that the concomitant use of proton pump inhibitors and methotrexate (primarily in high doses) may lead to an increase in the concentration of methotrexate and/or its metabolite hydroxymethotrexate and prolong its elimination time. However, no specific drug interaction studies of methotrexate with proton pump inhibitors have been conducted.

Storage Conditions

The drug should be stored in a dry, light-protected place, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years.

Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.