Pariet^® (Tablets) Instructions for Use

ATC Code

A02BC04 (Rabeprazole)

Active Substance

Rabeprazole (Rec.INN WHO registered)

Clinical-Pharmacological Group

H⁺-K⁺-ATPase inhibitor. Antiulcer drug

Pharmacotherapeutic Group

Gastric secretion reducing agent – proton pump inhibitor

Pharmacological Action

Mechanism of action

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

Rabeprazole sodium suppresses gastric acid secretion by specifically inhibiting H⁺-K⁺-ATPase at the secretory surface of the gastric parietal cells.

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 20 mg 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 the predictable T_1/2 (approximately one hour).

This effect can be explained by 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 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 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, 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 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 for omeprazole (20 mg/kg).

Not a single case of adenomatous changes or carcinoid tumors observed in rats was registered.

Other effects

Systemic effects of rabeprazole sodium on the CNS, cardiovascular or respiratory systems have not currently been detected.

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, as well as levels of cortisol, estrogens, testosterone, prolactin, glucagon, FSH, LH, renin, aldosterone and somatotropic hormone.

Pharmacokinetics

Absorption

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

Changes in 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 20 mg (compared to intravenous administration) is about 52%.

Furthermore, bioavailability does not change with repeated administration of rabeprazole.

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.

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

Neither the time of day of drug 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 extent of absorption changes.

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 sodium, 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 sodium is excreted in the feces.

Total excretion is 99.8%.

These data indicate minor excretion of rabeprazole sodium metabolites in bile.

The main metabolite is the thioether (M1).

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

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 sodium is similar to that in healthy volunteers.

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.

Drug clearance 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.

Elderly patients

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

After 7 days of taking rabeprazole 20 mg daily, 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.

CYP2C19 polymorphism

In patients with slow CYP2C19 metabolism after 7 days of taking rabeprazole at a dose of 20 mg daily, the AUC increases 1.9 times and C_max increases 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 gastroesophageal reflux disease or reflux esophagitis;
• Maintenance therapy of 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

Tablets

For gastric ulcer in the acute phase and anastomotic ulcer, it is recommended to take 20 mg orally 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 orally 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 (GERD) or reflux esophagitis, it is recommended to take 20 mg orally 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 orally 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 orally 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 once a day 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.

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

The duration of treatment is 7 days.

Patients with renal and hepatic impairment

Dose adjustment is not required for patients with renal impairment.

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 using in patients with severe hepatic impairment.

Elderly patients

Dose adjustment is not required.

Children

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 supported by extrapolation of results from 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.

Adverse Reactions

Adverse reactions are systematized by organ system using the following frequency classification: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), including isolated cases.

From the immune system rarely – acute systemic allergic reactions.

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

From metabolism and nutrition rarely – hypomagnesemia.

From the hepatobiliary system increased activity of liver enzymes; rarely – hepatitis, jaundice, hepatic encephalopathy.

From the urinary system very rarely – interstitial nephritis.

From the skin and subcutaneous tissues rarely – bullous rashes, urticaria; very rarely – erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.

From the musculoskeletal system rarely – myalgia, arthralgia.

From the reproductive system very rarely – gynecomastia.

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

According to post-marketing surveillance data, when taking PPIs, an increased risk of fractures, subacute cutaneous lupus erythematosus and fundic gland polyps is possible (see section “Special Precautions”).

Rare reports of hepatic encephalopathy have been received in patients with cirrhosis.

Contraindications

• Hypersensitivity to rabeprazole, substituted benzimidazoles or to the excipients of the drug;
• Pregnancy;
• Lactation period;
• Children under 12 years of age.

With caution

• In patients with severe renal failure;
• In childhood.

Use in Pregnancy and Lactation

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

Experimental studies of reproduction in rats and rabbits did not reveal signs of impaired fertility or fetal developmental defects due to rabeprazole; however, in rats, the drug penetrates the placental barrier in small quantities.

Should not be used during pregnancy except in cases where the expected positive effect for the mother outweighs the possible harm to the fetus.

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

Appropriate studies in nursing women have not been conducted.

However, Rabeprazole has been detected in the milk of lactating rats, and therefore Rabeprazole should not be prescribed to nursing women.

Use in Hepatic Impairment

Dose adjustment is not required for patients with hepatic impairment.

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

Use with caution in patients with severe hepatic impairment.

Use in Renal Impairment

Dose adjustment is not required for patients with renal impairment.

With caution use in patients with severe renal impairment.

Pediatric Use

Rabeprazole is contraindicated in children under 12 years of age, as there is currently no experience with its use in pediatric practice.

Geriatric Use

Dose adjustment is not required for elderly patients.

Special Precautions

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

Caution is recommended when first using rabeprazole in patients with severe liver dysfunction.

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

Dose adjustment is not required for patients with renal or hepatic impairment.

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 one year after therapy.

Serious adverse events were tetany, arrhythmia and convulsions.

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 concentration before starting PPI treatment and during treatment.

Other acid-reducing agents, such as H₂-receptor blockers or PPIs, should not be taken simultaneously.

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).

Concomitant use of rabeprazole with methotrexate

According to literature data, concomitant use of PPIs with methotrexate (primarily in high doses) may lead to an increase in the concentration of methotrexate and/or its metabolite hydroxymethotrexate and increase the T_1/2 period, which may lead to the manifestation of methotrexate toxicity.

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

Clostridium difficile

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

Subacute cutaneous lupus erythematosus (SCLE)

There are reports of cases of SCLE during PPI therapy.

If skin lesions appear, especially on areas of skin exposed to direct sunlight, and are accompanied by arthralgia, the patient should immediately seek medical help, and the healthcare professional should decide to discontinue rabeprazole therapy.

The occurrence of SCLE during previous PPI therapy may increase the risk of SCLE when taking 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 of gastrointestinal bleeding or small bowel obstruction.

The dosage and duration of PPI therapy for such patients should be minimal.

Effect on ability to drive vehicles and operate machinery

Based on the pharmacodynamic features of rabeprazole and its adverse effect profile, it is unlikely to affect the ability to drive a car and operate machinery.

However, if drowsiness occurs, these activities should be avoided.

Drug Interactions

Cytochrome P450 system

Rabeprazole sodium, like other PPIs, is metabolized with the participation of the cytochrome P450 (CYP450) system in the liver.

In in vitro studies on human liver microsomes, it was shown that Rabeprazole sodium is metabolized by the CYP2C19 and CYP3A4 isoenzymes.

Studies in healthy volunteers have shown that Rabeprazole sodium does not have 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. This four-way crossover study involved 16 healthy volunteers who received 20 mg of rabeprazole, 1000 mg of amoxicillin, 500 mg of 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-hydroxy-clarithromycin (an 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 causes sustained and prolonged suppression of gastric acid secretion. Therefore, interaction with substances for which 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 the need for dose adjustment when rabeprazole sodium is taken concomitantly with ketoconazole, digoxin, or other drugs for which absorption is pH-dependent.

Atazanavir

When atazanavir 300 mg/ ritonavir 100 mg was taken concomitantly with omeprazole (40 mg once daily) or atazanavir 400 mg with lansoprazole (60 mg once daily) by healthy volunteers, a significant decrease 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 PPIs. Therefore, concomitant use of atazanavir with PPIs, including Rabeprazole, is not recommended.

Antacids

In clinical studies, antacids were used concomitantly with rabeprazole sodium. Clinically significant interactions of rabeprazole sodium with aluminum hydroxide gel or magnesium hydroxide were not observed.

Food intake

In a clinical study during the administration of rabeprazole sodium with a low-fat meal, no clinically significant interactions were observed. Taking rabeprazole sodium concomitantly with a high-fat meal may delay the absorption of rabeprazole for up to 4 hours or more; however, C_max and AUC do not change.

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 taking 20 mg of rabeprazole. The degree of inhibition is similar to that for omeprazole at equivalent concentrations.

Methotrexate

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

Effect on laboratory test results

The use of PPIs leads to a decrease in gastric acidity, which can lead to an increase in chromogranin A (CgA) levels in the blood serum. An elevated CgA level may lead to erroneous interpretation of laboratory test results for the presence of a neuroendocrine tumor. To avoid this influence, the use of rabeprazole should be temporarily discontinued at least 14 days before assessing the CgA level; repeating the test should be considered if the baseline CgA level is high.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.