Rabelock, 20 mg 28 pcs.

Pharmacotherapeutic group: gastric gland secretion reducing agent – proton pump inhibitor.

The ATX code: A02BC04

Pharmacological properties

Pharmacodynamics

Mechanism of action

Rabeprazole sodium belongs to the class of antisecretory agents, benzimidazole derivatives. Rabeprazole sodium inhibits gastric juice secretion by specifically inhibiting H⁺/K⁺ATPase on the secretory surface of gastric parietal cells.

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

This effect is dose-dependent and results in suppression of both basal and stimulated acid secretion regardless of the stimulus. Rabeprazole sodium has no anticholinergic properties.

Antisecretory effects

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 is much longer than that predicted by the half-life (approximately one hour). This effect may be explained by prolonged binding of the drug substance to H⁺/ K⁺ATPase of gastric parietal cells.

The magnitude of the inhibitory effect of rabeprazole sodium on acid secretion reaches a plateau after three days of taking rabeprazole sodium. When discontinued, secretory activity is restored within 1-2 days.

The effect on plasma gastrin levels

In clinical studies, patients were treated with 10 or 20 mg of rabeprazole sodium daily for a treatment duration of up to 43 months. Plasma gastrin levels were elevated for the first 2 to 8 weeks, reflecting an inhibitory effect on acid secretion.

Gastrin concentrations returned to baseline levels usually within 1 to 2 weeks after discontinuation of treatment.

The effect on enterochromaffin-like cells

. In a study of human gastric biopsy specimens from the antrum and gastric fundus of 500 patients treated with rabeprazole sodium or a comparison drug for 8 weeks, no consistent changes were found in the morphological structure of enterochromaffin-like cells, gastritis severity, frequency of atrophic gastritis, intestinal metaplasia or the spread of Helicobacterpylori infection.

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 were reported in rats.

Systemic effects of rabeprazole sodium on the central nervous system, cardiovascular or respiratory systems have not been detected at this time.

Rabeprazole sodium has been shown to have no effect on thyroid function, carbohydrate metabolism, blood levels of parathyroid hormone, and levels of cortisol, estrogen, testosterone, prolactin, glucagon, follicle stimulating hormone (FSH), luteinizing hormone (LH), renin, aldosterone and somatotropic hormone when taken orally in a dose of 20 mg for 2 weeks.

Pharmacokinetics

Absorption

Rabeprazole is rapidly absorbed from the gut, and its peak plasma concentrations are reached approximately 3.5 h after a 20 mg dose. Changes in peak plasma concentrations (C_ma) and values of area under the concentration-time curve (AUC) 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%.

In addition, bioavailability does not change with repeated administration of rabeprazole. In healthy volunteers, the plasma elimination half-life is about 1 h (varying from 0.7 to 1.5 h) and total clearance is 3.8 ml/min/kg.

In patients with chronic liver damage, the AUC is doubled compared to healthy volunteers, indicating decreased first-pass metabolism, and the plasma elimination half-life is increased by 2 to 3 times.

Neither the time of intake of the drug during the day, nor antacids affect absorption of rabeprazole. Taking the drug with fatty foods slows down absorption of rabeprazole by 4 hours or more, but neither C_mah nor the degree of absorption is changed.

Distribution

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

Metabolism and excretion

In healthy subjects

After a single oral dose of 20 mg ¹⁴C-labeled sodium rabeprazole, no unchanged drug was found in the urine. About 90% of rabeprazole is excreted in the urine mainly as two metabolites: conjugatamercapturic acid (M5) and carboxylic acid (M6), and in the form of two unknown metabolites identified in the toxicological analysis. The remainder of rabeprazole sodium taken is excreted in the feces.

The total excretion is 99.8%. These data indicate a small excretion of metabolites of sodium rabeprazole with bile. The main metabolite is thioether (M1). The only active metabolite is desmethyl (M3), but it was observed in low concentration only in one study participant after administration of 80 mg of rabeprazole.

Terminal renal failure

In patients with stable, terminal renal failure who require maintenance hemodialysis (creatinine clearance <5 ml/min/1.73m²), the excretion of rabeprazole sodium is similar to that of healthy volunteers. The AUC and C_max in these patients were approximately 35% lower than in healthy volunteers.

The mean half-life of rabeprazole was 0.82 h in healthy volunteers, 0.95 h in patients during hemodialysis, and 3.6 h after hemodialysis. Clearance of the drug in patients with kidney disease requiring hemodialysis was approximately twice as high as in healthy volunteers.

Chronic compensated cirrhosis

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

Elderly patients

In elderly patients, elimination of rabeprazole is somewhat delayed. After 7 days of taking rabeprazole at 20 mg daily, the AUC was approximately twice as high and the C_max was increased by 60% compared to young healthy volunteers. However, no evidence of rabeprazole cumulation was observed.

CYP2C19 polymorphism

. In patients with delayed CYP2C19 metabolism after 7 days of taking rabeprazole at a dose of 20 mg per day, the AUC is increased 1.9-fold and the elimination half-life 1.6-fold compared to the same parameters in “fast metabolizers”, while C_max is increased by 40%.

Indications

– Gastric ulcer in the acute stage and anastomosis ulcer;

– Duodenal ulcer in the acute stage;

– erosive and ulcerative 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 therapy:

– eradication of Helicobacterpylori in patients with peptic ulcer disease.

Active ingredient

Rabeprazole

Composition

1 tablet contains:

The active ingredient:rabeprazole sodium 20 mg.

Excipients: mannitol 89.0 mg; magnesium oxide 80.0 mg; hypromellose5.0 mg; microcrystalline cellulose 20.0 mg; starch 20.0 mg; carmellose 20.0 mg; talc 3.0 mg; magnesium stearate 6.0 mg; colloidal silicon dioxide 3.0 mg.

The shell: hypromellose 9.5 mg; propylene glycol 1.5 mg;

The enteric coating:methacrylic acid and ethylacrylate copolymer (type C) (1:1) 13.95 mg; polysorbate 80 0.209 mg; dibutyl phthalate 2.090 mg; sodium hydroxide 0.119 mg; iron oxide yellow dye 0.783 mg; talc 5.63 mg; titanium dioxide 1.210 mg.

How to take, the dosage

Tablets of Rabelock^® should not be chewed or crushed. The tablets should be swallowed whole. It has been found that neither time of day nor food intake affects the activity of Rabeprazole sodium.

In acute peptic ulcer disease and anastomosis ulcer, it is recommended to take orally 20 mg once daily. Usually cure occurs after 6 weeks of therapy, but in some cases the duration of treatment can be extended for another 6 weeks.

In case of duodenal ulcer in the acute stage, it is recommended to take orally 20 mg once a day. The duration of treatment is from 2 to 4 weeks. If necessary, the treatment duration can be extended for 4 more weeks.

In the treatment of erosive gastroesophageal reflux disease (GERD) or reflux esophagitis it is recommended to take orally 20 mg once a day. The duration of treatment is 4 to 8 weeks. If necessary, the duration of treatment may be increased for 8 more weeks.

In maintenance therapy of gastroesophageal reflux disease (GERD) it is recommended to take orally 20 mg once a day. The duration of treatment depends on the patient’s condition.

In non-erosive gastroesophageal reflux disease (NERD) without esophagitis, oral administration of 20 mg once daily is recommended.

If symptoms persist after four weeks of treatment, further investigation of the patient should be performed.

After symptoms have resolved, oral medication should be taken once daily on demand to prevent future symptoms.

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

The starting dose is 60 mg per day, and then the dose is increased to 100 mg per day on a single dose or 60 mg twice a day. For some patients, fractional dosing is preferable.

Treatment should continue as clinically necessary. In some patients with Zollinger-Elison syndrome, the duration of treatment with rabeprazole was up to one year.

For eradication of Helicobacterpylori it is recommended to take orally 20 mg 2 times a day according to a certain scheme with an appropriate combination of antibiotics. The duration of treatment is 7 days.

Patients with renal and hepatic impairment

Dose adjustment is not required in patients with renal impairment.

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

Patients with severe hepatic impairment should use caution when prescribing Rabelock^®.

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 adequate and well-controlled studies supporting the effectiveness of rabeprazole sodium for adults and safety and pharmacokinetics studies for pediatric patients.

The recommended dose for children aged 12 years and older is 20 mg once daily 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. Safety and efficacy of rabeprazole sodium for use for other indications has not been established for pediatric patients.

Interaction

The cytochrome 450 system

Sodium rabeprazole, like other proton pump inhibitors (PPIs), is metabolized with the cytochrome P450 system (CYP450) in the liver. In in-vitro studies on human liver microsomes it has been shown that rabeprazole sodium is metabolized by CYP2C19 and CYP3A4 isoenzymes.

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

There has been a study of combination therapy with antibacterial drugs. 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 to monotherapy. The AUC and C_max rates for rabeprazole increased by 11% and 34%, respectively, and the AUC and C_max rates for 14-hydroxy clarithromycin (the active metabolite of clarithromycin) increased by 42% and 46%, respectively, for combination therapy compared with monotherapy.

This increase in exposure rates for rabeprazole and clarithromycin was not found to be clinically significant.

Interactions due to inhibition of gastric juice secretion

Rabeprazole sodium has sustained and prolonged inhibition of gastric juice secretion. Thus, there may be an interaction with substances for which absorption is pH-dependent. When concomitant administration with rabeprazole sodium absorption of ketoconazole is reduced by 30%, and absorption of digoxin is increased by 22%.

Hence, some patients should be monitored to decide if a dose adjustment is necessary when concomitantly taking rabeprazole sodium with ketoconazole, digoxin or other drugs for which absorption is pH dependent.

Atazanavir

Atazanavir 300 mg / ritonavir 100 mg concomitantly taken with omeprazole (40 mg once daily) or atazanavir 400 mg with lansoprazole (60 mg once daily) in healthy volunteers showed significant reduction in atazanavir exposure.

The absorption of atazanavir is pH dependent. Although concomitant administration with rabeprazole has not been studied, similar results are also expected for other proton pump inhibitors. Thus, concomitant administration of atazanavir with proton pump inhibitors, including rabeprazole, is not recommended.

Antacids

In clinical studies, antacids have been used together with rabeprazole sodium. No clinically significant interactions of rabeprazole sodium with aluminum hydroxide gel or with magnesium hydroxide were observed.

In a clinical study during administration of rabeprazole sodium with fat-dense foods no clinically significant interactions were observed. Taking rabeprazole sodium concomitantly with fat-rich foods may delay absorption of rabeprazole for 4 hours or more, but C_max and AUC are not altered.

Cyclosporine

Experiments using human liver microsomes showed that rabeprazole inhibited the metabolism of cyclosporine with an IC₅₀ of 62 μmol, ie. i.e., at a concentration 50 times the C_max for healthy volunteers after 14 days of taking 20 mg of rabeprazole. The degree of inhibition is similar to that of omeprazole for equivalent concentrations.

Methotrexate

The adverse event reports, published pharmacokinetic studies and retrospective data suggest that concomitant administration of PPIs and methotrexate (especially in high doses) can increase methotrexate and/or its metabolite hydroxytetrexate concentrations and prolong the elimination half-life.

However, there have been no specific studies of drug interactions between methotrexate and PPIs.

Introduction of PPIs leads to a decrease in gastric acidity, which may lead to an increase in chromogranin A (CgA) in the serum. Increased levels of CgA may lead to misinterpretation of the results of laboratory tests for the presence of a neuroendocrine tumor.

To avoid this effect, use of Rabelock^® should be temporarily discontinued at least 14 days before CgA levels are evaluated; a repeat test should be considered if baseline CgA levels are high.

Special Instructions

Patient response to therapy with rabeprazole sodium does not rule out the presence of gastric malignancy. Tablets of Rabelock^® should not be chewed or crushed. The tablets should be swallowed whole. It has been found that neither time of day nor food intake affect the activity of Rabeprazole sodium.

In a special study in patients with mild to moderate hepatic impairment, there was no significant difference in the incidence of side effects of Rabelock^® compared to that in gender- and age-matched healthy subjects, but despite this, caution is recommended when first prescribing Rabelock® in patients with severe hepatic impairment. The AUC of rabeprazole sodium in patients with severe hepatic impairment is approximately twice as high as in healthy patients.

Patients with impaired renal or hepatic function do not require dose adjustment of Rabelock®.

Hypomagnesemia

In treatment with proton pump inhibitors for at least 3 months, cases of symptomatic or asymptomatic hypomagnesemia have rarely been reported. Most of these cases were reported one year after therapy.

Serious adverse events were tetany, arrhythmias, and seizures. Most patients required treatment for hypomagnesemia, which included magnesium replacement and withdrawal of proton pump inhibitor therapy. In patients who will receive long-term treatment or who take proton pump inhibitors with drugs such as digoxin or drugs that can cause hypomagnesemia (such as diuretics), health care providers should monitor magnesium levels before treatment with proton pump inhibitors and during treatment.

Patients should not take other acid reducing agents such as H₂ receptor blockers or proton pump inhibitors at the same time as Rabelock®.

Bone fractures

An observational study suggests that therapy with proton pump inhibitors (PPIs) may increase the risk of osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high doses of PPIs for a long time (one year or more).

The concomitant use of rabeprazole with methotrexate

According to the literature, concomitant use of PPIs with methotrexate (especially in high doses) may lead to increased concentrations of methotrexate and/or its metabolite hydroxy-methotrexate and increase the elimination half-life, which may lead to methotrexate toxicity. Temporary discontinuation of PPI therapy may be considered if high doses of methotrexate are necessary.

Clostridiumdifficile

PPPI therapy may increase the risk of gastrointestinal infections such as Clostridiumdifficile.

Serious cutaneous lupus erythematosus (SLE)

There have been reports of SLE during PPI therapy. If skin lesions appear, especially on areas of skin exposed to direct sunlight and accompanied by arthralgia, the patient should seek medical attention immediately, and the healthcare professional should decide to discontinue therapy with rabeprazole.

The occurrence of PCOS on previous PPI therapy may increase the risk of PCOS on other PPIs.

Glandular floor polyps

Long-term use of PPIs, including rabeprazole, appears to be associated with an increased risk of glandular floor polyps. Most glandular polyps of the stomach floor are asymptomatic. Patients with large or ulcerated polyps may be at risk for gastrointestinal bleeding or small intestinal obstruction.

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

Impact on the ability to drive or operate machinery

Based on the pharmacodynamics of rabeprazole and its adverse effect profile, it is unlikely that the drug Rabelock® has an effect on the ability to drive or operate machinery. However, in case of drowsiness, these activities should be avoided.

Contraindications

Individual hypersensitivity to rabeprazole, substituted benzimidazoles or excipients of the drug, pregnancy, breastfeeding, children under 12 years of age.

With caution

Severe renal insufficiency, severe hepatic insufficiency, children under 12 to 18 years of age.

Side effects

Based on the experience of clinical studies, it can be concluded that rabeprazole is usually well tolerated by patients. Side effects, generally mild to moderate, are transient. The following adverse effects have been reported during clinical trials when taking rabeprazole: headache, abdominal pain, diarrhea, flatulence, constipation, dry mouth, dizziness, rash, peripheral edema.

The adverse reactions are systematized relative to each of the organ systems using the following frequency classification: Very common (>1/10); common (>1/100 and <1/10); infrequent (>1/1000 and <1/100); rare (>1/10000 and <1/1000); very rare (<1/10000), including isolated cases.

Immune system disorders: rare – acute systemic allergic reactions.

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

Disorders of metabolism and nutrition: rarely – hypomagnesemia.

Hepatic and biliary tract disorders: increased activity of liver enzymes, rarely – hepatitis, jaundice, hepatic encephalopathy.

Renal and urinary tract disorders: very rare – interstitial nephritis.

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

Muscular and connective tissue disorders: rarely – myalgia and arthralgia.

Gender and mammary gland disorders: very rare – gynecomastia.

There were no changes in other laboratory parameters during administration of Rabeprazole sodium.

According to the data of post-marketing observations with proton pump inhibitors (PPIs) there may be an increased risk of fractures, subacute cutaneous lupus erythematosus and glandular polyps of the stomach floor (see section “Cautions”). Rare reports of hepatic encephalopathy have been reported in patients with cirrhosis.

Overdose

Symptoms. Reports of overdose are minimal. Rabeprazole doses of 60 mg twice daily and 160 mg once daily have been reported. Side effects were minimal and did not require medical intervention.

Treatment. A specific antidote is not known. Rabeprazole binds well to plasma proteins and is therefore poorly excreted by dialysis.

In case of overdose symptomatic treatment is necessary.

Pregnancy use

There are no data on the safety of rabeprazole administration during pregnancy. Reproduction studies in rats and rabbits have shown no evidence of fertility abnormalities or fetal defects caused by rabeprazole; however, in rats, small amounts of the drug penetrate the placental barrier.

Rabelock^® should not be used in pregnancy unless the expected benefits to the mother outweigh the possible harm to the fetus.

It is not known whether rabeprazole is excreted with the breast milk. Corresponding studies in breastfeeding women were not conducted. However, rabeprazole is found in the milk of lactating rats, and therefore Rabelock^® should not be prescribed to nursing women.

Similarities

Pariet, Zulbecs, Hirabezol, Rabelock, Rabeprazol, Razo, Rabiet , Irritable bowel