Rabeprazole-SZ (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

Acid-related disorder treatment agents; antiulcer agents and agents for the treatment of gastroesophageal reflux disease (GERD); proton pump inhibitors

Pharmacological Action

Mechanism of action and pharmacodynamic effects

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

Clinical efficacy and safety

Antisecretory effect

After oral administration of 20 mg of rabeprazole sodium, the antisecretory effect develops within one 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 that predictable from 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 recovers within 1-2 days.

Effect on plasma gastrin levels

In clinical studies, patients took 10 or 20 mg of rabeprazole sodium daily for up to 43 months. Plasma gastrin levels were elevated for the first 2-8 weeks, reflecting the inhibitory effect on acid secretion. Gastrin concentrations 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 treated with Rabeprazole sodium or a comparator drug for 8 weeks, 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 not detected.

In a study involving more than 400 patients treated with 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

Systemic effects of rabeprazole sodium on the central nervous, cardiovascular, or respiratory systems have not been detected to date. It has been shown that Rabeprazole sodium, when taken orally at a dose of 20 mg for 2 weeks, does not affect thyroid function, carbohydrate metabolism, blood parathyroid hormone levels, or levels of cortisol, estrogens, testosterone, prolactin, glucagon, FSH, LH, renin, aldosterone, and somatotropic hormone.

Pharmacokinetics

Absorption

Rabeprazole is rapidly absorbed from the intestine, C_max in plasma is reached approximately 3.5 hours after a 20 mg dose. The absolute bioavailability after oral administration of a 20 mg dose (compared to intravenous administration) is about 52%. Furthermore, bioavailability does not change with repeated administration of rabeprazole.

Neither the time of day of drug administration nor antacids affect the absorption of rabeprazole. Taking the drug with fatty food slows the absorption of rabeprazole by 4 hours or more, but neither C_max nor the extent of absorption is changed.

Distribution

In humans, the degree of binding of rabeprazole to plasma proteins is about 97%.

Metabolism and excretion

In healthy individuals. After a single oral dose of 20 mg of ¹⁴C-labeled rabeprazole, no unchanged drug was found in the urine. About 90% of rabeprazole is excreted in the urine mainly as 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 is excreted in the feces.

Total excretion is 99.8%. These data indicate minor excretion of rabeprazole metabolites in the bile. The main metabolite is the thioether (M1). The only active metabolite is desmethyl (M3), but it was observed at low concentration in only one study participant after taking rabeprazole at a dose of 80 mg.

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

Linearity (non-linearity)

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

Pharmacokinetics in special patient groups

End-stage renal failure. In patients with stable end-stage renal failure requiring maintenance hemodialysis (CrCl <5 ml/min/1.73 m²), the excretion of rabeprazole is similar to that in healthy volunteers. The AUC and C_max in these patients were approximately 35% lower than in healthy volunteers. The mean 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. The clearance of the drug in patients with kidney disease requiring hemodialysis was approximately 2 times higher than in healthy volunteers.

Chronic compensated cirrhosis. 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 patients with chronic liver disease, the AUC is doubled compared to healthy volunteers, indicating a reduced first-pass effect, and the plasma T_1/2 is increased 2-3 times.

Elderly patients. In elderly patients, the elimination of rabeprazole is somewhat slowed. After 7 days of taking rabeprazole 20 mg/day, the AUC in elderly patients 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.

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

Indications

Adults aged 18 years and over

• Gastric ulcer in the acute phase and anastomotic ulcer;
• Duodenal ulcer in the acute phase;
• Erosive and ulcerative gastroesophageal reflux disease (GERD) or reflux esophagitis;
• Maintenance therapy for GERD;
• Non-erosive gastroesophageal reflux disease (NERD);
• 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.

Children aged 12 to 18 years

• Erosive and ulcerative GERD or reflux esophagitis

ICD codes

Dosage Regimen

Capsules

Orally. The capsules of the drug Rabeprazole-SZ should be swallowed whole. It has been established that neither the time of day nor food intake affects the activity of rabeprazole sodium.

Adults

Gastric ulcer in the acute phase and anastomotic ulcer

The recommended dose is 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.

Duodenal ulcer in the acute phase

The recommended dose is 20 mg once a day. The duration of treatment is 2-4 weeks. If necessary, the duration of treatment can be extended for another 4 weeks.

Erosive and ulcerative GERD or reflux esophagitis

The recommended dose is 20 mg once a day. The duration of treatment is 4-8 weeks. If necessary, the duration of treatment can be extended for another 8 weeks.

Maintenance therapy for GERD

The recommended dose is 20 mg once a day. The duration of treatment depends on the patient’s condition.

NERD

The recommended dose is 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.

Zollinger-Ellison syndrome and other conditions with 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 as a single dose or 60 mg twice a day. For some patients, divided dosing of the drug is preferable. Treatment should continue as clinically necessary. In some patients with Zollinger-Ellison syndrome, the duration of treatment with rabeprazole was up to 1 year.

Eradication of Helicobacter pylori

The recommended dose is 20 mg twice a day according to a specific regimen with an appropriate combination of antibiotics. The duration of treatment is 7 days.

Special patient groups

Patients with impaired renal function. Dose adjustment is not required for patients with impaired renal function. Caution should be exercised when prescribing the drug Rabeprazole-SZ to patients with severe renal impairment.

Patients with impaired hepatic function. In patients with mild to moderate hepatic impairment, blood concentrations of rabeprazole are usually higher than in healthy volunteers. Caution should be exercised when prescribing the drug Rabeprazole-SZ to patients with severe hepatic impairment.

Elderly patients. Dose adjustment is not required.

Children and adolescents

Children aged 12 to 18 years

The safety and efficacy of rabeprazole at a dose of 20 mg for short-term (up to 8 weeks) treatment of GERD in children aged 12 years and older is supported by extrapolation from adequate and well-controlled studies supporting the efficacy of rabeprazole in adults and safety and pharmacokinetic studies in children.

The recommended dose is 20 mg once a day for up to 8 weeks.

The safety and efficacy of the drug Rabeprazole-SZ for use in children for other indications has not been established.

Children aged 0 to 12 years

The safety and efficacy of rabeprazole for the treatment of GERD in children aged 0 to 12 years has not been established. The safety and efficacy of rabeprazole for use for other indications has not been established for pediatric patients.

Adverse Reactions

Based on clinical trial experience, it can be concluded that the drug Rabeprazole-SZ is generally well tolerated by patients. Side effects are generally mild or moderate and are transient.

In clinical trials, the following adverse reactions were noted when taking rabeprazole: headache, abdominal pain, diarrhea, flatulence, constipation, dry mouth, dizziness, rash, peripheral edema.

Adverse reactions are systematized according to the WHO classification: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); frequency unknown (cannot be estimated from the available data).

Blood and lymphatic system disorders rare – thrombocytopenia, neutropenia, leukopenia.

Immune system disorders rare – acute systemic allergic reactions.

Metabolism and nutrition disorders rare – hypomagnesemia.

Hepatobiliary disorders rare – hepatitis, jaundice, hepatic encephalopathy.

Skin and subcutaneous tissue disorders rare – bullous eruptions, urticaria; very rare – erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders rare – myalgia, arthralgia.

Renal and urinary disorders very rare – risk of acute tubulointerstitial nephritis (with possible progression to renal failure); frequency unknown – erectile dysfunction.

Reproductive system and breast disorders very rare – gynecomastia.

Laboratory and instrumental data increased activity of liver enzymes, changes in other parameters were not observed when taking rabeprazole.

Description of selected adverse reactions

According to post-marketing surveillance data, when taking proton pump inhibitors (PPIs), an increased risk of fractures, subacute cutaneous lupus erythematosus, and fundic gland polyps may be possible (see section “Special Precautions”). Rare reports of hepatic encephalopathy have been received in patients with cirrhosis.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to rabeprazole, substituted benzimidazoles, or to the excipients of the drug;
• Pregnancy;
• Breastfeeding period.

Use in Pregnancy and Lactation

Pregnancy

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

Reproductive studies in rats and rabbits did not reveal any signs of impaired fertility or fetal developmental defects due to rabeprazole; however, in rats, the drug crosses the placental barrier in small amounts. The drug Rabeprazole-SZ is contraindicated for use during pregnancy.

Breastfeeding period

It is not known whether Rabeprazole is excreted in breast milk. Appropriate studies on the use of the drug during breastfeeding have not been conducted. However, Rabeprazole has been found in the milk of lactating rats, therefore the drug Rabeprazole-SZ is contraindicated for use in women during breastfeeding.

Use in Hepatic Impairment

Dose adjustment of the drug Rabeprazole-SZ is not required for patients with impaired hepatic function.

The drug should be prescribed with caution in severe hepatic insufficiency.

Use in Renal Impairment

Dose adjustment of the drug Rabeprazole-SZ is not required for patients with impaired renal function.

The drug should be prescribed with caution in severe renal insufficiency.

Pediatric Use

The use of the drug is contraindicated under the age of 18 years, except for GERD (children under 12 years of age).

Geriatric Use

Dose adjustment in elderly patients is not required.

Special Precautions

The patient’s response to rabeprazole therapy does not rule out the presence of malignant neoplasms in the stomach.

Hepatic insufficiency

In a special study in patients with mild or moderate hepatic impairment, no significant difference in the frequency of adverse effects of rabeprazole sodium from that in age- and sex-matched healthy individuals was found; nevertheless, caution is recommended when first prescribing the drug Rabeprazole-SZ to patients with severe hepatic impairment. The AUC of rabeprazole sodium in patients with severe hepatic impairment is approximately 2 times higher than in healthy patients.

Dose adjustment of the drug Rabeprazole-SZ is not required for patients with impaired renal or hepatic function.

Renal insufficiency

Dose adjustment of the drug Rabeprazole-SZ is not required for patients with impaired renal function. The drug Rabeprazole-SZ should be prescribed with caution to patients with severe renal insufficiency.

Hypomagnesemia

During treatment with PPIs for at least 3 months, cases of symptomatic or asymptomatic hypomagnesemia have been rarely reported. In most cases, these reports were received after one year of therapy. Serious adverse events were tetany, arrhythmia, and seizures. Most patients required treatment for hypomagnesemia, including magnesium replacement and discontinuation of PPI therapy. In patients who will receive long-term treatment or who are taking PPIs with drugs such as digoxin, or drugs that can cause hypomagnesemia (e.g., diuretics), healthcare professionals should monitor magnesium levels before starting PPI treatment and during treatment. Patients should not take other acid-reducing agents, such as histamine H₂-receptor blockers or proton pump inhibitors, concomitantly with the drug Rabeprazole-SZ.

Bone fractures

According to observational studies, it can be assumed that PPI therapy may lead to an increased risk of osteoporosis-related fractures of the hip, wrist, or spine. The risk of fractures was increased in patients receiving high doses of PPIs for a long time (a year or more).

Clostridium difficile

PPI therapy may lead to an increased risk of gastrointestinal infections, such as Clostridium difficile infection.

Subacute Cutaneous Lupus Erythematosus (SCLE)

There have been reports of SCLE with PPI therapy. If skin lesions appear, especially on sun-exposed skin areas, and are accompanied by arthralgia, the patient should seek medical advice immediately; the healthcare professional should consider discontinuing rabeprazole therapy. The occurrence of SCLE with previous PPI therapy may increase the risk of SCLE with other PPIs.

Fundic Gland Polyps

Long-term use of PPIs, including Rabeprazole, appears to be associated with an increased risk of fundic gland polyps. Most fundic gland polyps are asymptomatic. Patients with large or ulcerated polyps may be at risk for gastrointestinal bleeding or small bowel obstruction. The dose and duration of PPI therapy for such patients should be minimized.

Concomitant use of rabeprazole with methotrexate

According to literature, concomitant administration of PPIs with methotrexate (primarily at high doses) may lead to increased concentrations of methotrexate and/or its metabolite hydroxymethotrexate and increase T_1/2, which may lead to methotrexate toxicity. When high-dose methotrexate is necessary, temporary discontinuation of PPI therapy may be considered.

Excipients

The drug Rabeprazole-SZ contains sugar spheres (sucrose, starch syrup). Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicine.

Effect on ability to drive and use machines

Rabeprazole-SZ has no or negligible influence on the ability to drive and use machines. However, if drowsiness occurs, these activities should be avoided.

Overdose

Data on deliberate or accidental overdose are limited. No cases of severe rabeprazole overdose have been reported.

Treatment No specific antidote for rabeprazole is known. Rabeprazole is highly bound to plasma proteins and is therefore not readily dialyzable. In case of overdose, symptomatic and supportive treatment should be given.

Drug Interactions

Cytochrome P450 system

Rabeprazole sodium, like other PPIs, 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 interactions 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 crossover 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 (the active metabolite of clarithromycin), 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 produces sustained and prolonged inhibition of gastric acid secretion. Thus, an interaction with substances whose absorption is pH-dependent may occur. When co-administered with rabeprazole sodium, the absorption of ketoconazole is decreased by 30%, and the absorption of digoxin is increased by 22%. Therefore, for some patients, monitoring should be considered to assess the need for dose adjustment when rabeprazole sodium is co-administered with ketoconazole, digoxin, or other drugs whose absorption is pH-dependent.

Histamine H₂-receptor antagonists or other PPIs

Patients should not take other acid-reducing agents, such as histamine H₂-receptor antagonists or other PPIs, concomitantly with Rabeprazole-SZ.

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 substantial reduction in atazanavir exposure was observed. The absorption of atazanavir is pH-dependent. Although co-administration with rabeprazole has not been studied, similar results are expected for other proton pump inhibitors. Therefore, co-administration 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 of rabeprazole sodium with aluminum hydroxide gel or magnesium hydroxide was observed.

Food intake

In a clinical study with rabeprazole sodium administered with a low-fat meal, no clinically significant interaction was observed. Administration of 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 altered.

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 14 days of dosing with 20 mg rabeprazole. The degree of inhibition is similar to that for omeprazole at equivalent concentrations.

Methotrexate

Based on adverse event reports, published pharmacokinetic study data, and retrospective analysis data, it can be assumed that concomitant administration of PPIs and methotrexate (primarily at high doses) may lead to increased concentrations of methotrexate and/or its metabolite hydroxymethotrexate and increase T_1/2, which may lead to methotrexate toxicity. However, no specific drug interaction studies of methotrexate with PPIs have been conducted.

When high-dose methotrexate is necessary, temporary discontinuation of PPI therapy may be considered.

Effect on laboratory tests

Use of PPIs leads to a decrease in gastric acidity, which may lead to an increase in serum chromogranin A (CgA) levels. An elevated CgA level may lead to misinterpretation of laboratory test results for neuroendocrine tumors. To avoid this influence, the use of Rabeprazole-SZ should be temporarily discontinued at least 14 days prior to assessing CgA levels; a repeat test should be considered if the initial CgA level is high.

Storage Conditions

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

Shelf Life

The shelf life is 3 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.