Universal reference book for medicines
Product name: RABIET ® (RABIET)

Active substance: rabeprazole

Type: H + -K + -ATPase inhibitor.
Antiulcer drug
Manufacturer: ФП ОБОЛЕНСКОЕ (Russia)
Composition, form of production and packaging
Intestine-soluble
hard gelatine capsules, size 1, with a blue casing and lid;
the contents of the capsules are spherical pellets from almost white to white with a creamy or yellowish hue of color.
1 caps.

rabeprazole sodium * 20 mg

* Rabeprazole, substance-pellets 8.5% - 236 mg.

[PRING] sugar spheres (sucrose - 99.83%, povidone - 0.17%) - 142.92 mg, sodium carbonate - 3.32 mg, talc - 3.54 mg, titanium dioxide - 1.66 mg, hypromellose - 29.5 mg.

Auxiliary substances for the pellet shell: hypromellose phthalate - 31.88 mg, cetyl alcohol - 3.18 mg.

The composition of the capsule of hard gelatin № 1: the capsule body and capsule - titanium dioxide - 2%, the dye is blue patented - 0.0158%, gelatin - up to 100%.

5 pieces.
- packings of cellular contour (1, 2, 3) - packs cardboard.
7 pcs.
- packings of cellular contour (1, 2, 3) - packs cardboard.
10 pieces.
- packings of cellular contour (1, 2, 3) - packs cardboard.
14 pcs.
- packings of cellular contour (1, 2, 3) - packs cardboard.
15 pcs.
- packings of cellular contour (1, 2, 3) - packs cardboard.
20 pcs.
- packings of cellular contour (1, 2, 3) - packs cardboard.
30 pcs.
- packings of cellular contour (1, 2, 3) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2016.

PHARMACHOLOGIC EFFECT

H + -K + -ATPase inhibitor.
Antiulcer drug.
Mechanism of action

Rabeprazole sodium belongs to the class of antisecretory compounds, derivatives of benzimidazole.
Rabeprazole sodium suppresses the secretion of gastric juice by specific inhibition of H + / K + ATPase on the secretory surface of parietal cells of the stomach. H + / K + ATPase is a protein complex that functions as a proton pump, so rabeprazole sodium is an inhibitor of the proton pump in the stomach and blocks the final stage of acid production. This effect is dose-dependent and leads to suppression of both basal and stimulated acid secretion irrespective of the stimulus. Rabeprazole sodium does not possess anticholinergic properties.
Antisecretory action

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 is much exceeds the predicted value for T 1/2 (about 1 hour).
This effect can be explained by the prolonged binding of the drug substance to the H + / K + ATPase of parietal cells of the stomach. The magnitude of the inhibitory effect of rabeprazole sodium on acid secretion reaches a plateau after 3 days of taking rabeprazole sodium. At the termination of reception secretory activity is restored within 1-2 days.
Effect on the concentration of gastrin in blood plasma

In clinical trials, patients took rabeprazole sodium at doses of 10 or 20 mg daily for a treatment duration of up to 43 months.
The concentration of gastrin in the blood plasma was increased in the first 2-8 weeks, which reflects the inhibitory effect on acid secretion. The concentration of gastrin returned to baseline usually within 1-2 weeks after discontinuation of treatment.
Effect on enterochromaffin-like cells

In the study of human stomach biopsy specimens from the antrum and stomach bottom area of ​​500 patients treated with rabeprazole sodium or a reference preparation for 8 weeks, stable changes in the morphological structure of enterochromaxin-like cells, the degree of gastritis, the frequency of atrophic gastritis, intestinal metaplasia or the spread of Helicobacter pylori 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 of omeprazole (20 mg / kg).
There were no cases of adenomatous changes or carcinoid tumors observed in rats.
Other effects

The systemic effects of rabeprazole sodium on the CNS, cardiovascular or respiratory systems are not currently detected.
It was shown that rabeprazole sodium ingestion at a dose of 20 mg for 2 weeks does not affect the function of the thyroid gland, carbohydrate metabolism, the concentration of parathyroid hormone in the blood, as well as the concentration of cortisol, estrogens, testosterone, prolactin, glucagon, FSH, LH , renin, aldosterone and growth hormone.
PHARMACOKINETICS

Suction and distribution

Rabeprazole is rapidly absorbed from the intestine, C max in the blood plasma is achieved approximately 3.5 hours after taking a dose of 20 mg.
Changing C max in blood plasma, the values ​​of AUC of rabeprazole are linear in the dose range of 10 to 40 mg. Absolute bioavailability after oral administration at a dose of 20 mg (compared with the intravenous administration) is about 52%. In addition, bioavailability does not change with multiple administration of rabeprazole. Neither the time of taking the drug during the day, nor antacids affect the absorption of rabeprazole. The intake of the preparation with fatty food slows the absorption of rabeprazole by 4 hours or more, however, neither C max nor the degree of absorption is changed.
The binding of rabeprazole to plasma proteins is about 97%.

Metabolism

The main metabolite is thioester (M1).
The only active metabolite is desmethyl (M3), but it was determined in a low concentration only in one participant in the study after taking rabeprazole at a dose of 80 mg.
After a single admission of 14 C-labeled rabeprazole sodium at a dose of 20 mg unchanged drug in the urine was not detected.
About 90% of rabeprazole is excreted through the kidneys mainly in the form of two metabolites: the conjugate of mercapturic acid (M5) and the carboxylic acid (M6), and also in the form of two unknown metabolites detected during the toxicological analysis. The rest of the accepted rabeprazole sodium is excreted through the intestine.
The total excretion is 99.8%.
These data indicate a slight excretion of metabolites of rabeprazole sodium with bile.
In healthy volunteers, T 1/2 from the plasma is about 1 hour (varying from 0.7 to 1.5 hours), the total clearance is 3.8 ml / min / kg.

Pharmacokinetics in specific patient groups

In patients with chronic liver disease, AUC is doubled compared to healthy volunteers, which indicates a decrease in metabolism in the "first pass," and T 1/2 from the blood plasma is increased by 2-3 times.

In patients with stable renal insufficiency in the terminal stage, which require maintenance hemodialysis (CC <5 ml / min / 1.73 m 2 ), removal of rabeprazole sodium is similar to that of healthy volunteers.
AUC and C max in these patients were approximately 35% lower than in healthy volunteers. On average, T 1/2 rabeprazole was 0.82 h in healthy volunteers; 0.95 h - in patients during hemodialysis and 3.6 h after hemodialysis. The clearance of the drug in patients with diseases of the kidneys in need of hemodialysis was approximately 2 times higher than in healthy volunteers.
Patients with chronic compensated cirrhosis transfer rabeprazole sodium at a dose of 20 mg 1 time / day, although 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 down.
After 7 days of 20 mg daily rabeprazole in elderly people, AUC was approximately twice as high , and C max was increased by 60% compared to young healthy volunteers. However, there were no signs of cumulation of rabeprazole.
In patients with delayed metabolism of CYP2C19 after 7 days of rabeprazole at a dose of 20 mg / day, the AUC increases 1.9 times, and T 1/2 - 1.6 times compared with the same parameters in "fast metabolizers," while C max increases by 40%.

INDICATIONS

- Stomach ulcer in the phase of exacerbation and an anastomosis ulcer;

- Duodenal ulcer in the phase of exacerbation;

- 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 with appropriate antibiotic therapy for the eradication of Helicobacter pylori in patients with peptic ulcer.

DOSING MODE

The drug is taken orally.
Capsules should be swallowed whole, not chewing or grinding. It has been established that neither the time of day nor the intake of food affects the activity of rabeprazole sodium.
With gastric ulcer in the phase of exacerbation and ulcer of anastomosis, it is recommended to take 20 mg 1 time / day.
Usually, the cure comes after 6 weeks of therapy, but in some cases the duration of treatment can be increased by another 6 weeks.
With peptic ulcer of the duodenum in the acute phase, it is recommended to take 20 mg 1 time / day.
Duration of treatment is from 2 to 4 weeks. If necessary, the duration of treatment can be increased by another 4 weeks.
In the treatment of erosive gastroesophageal reflux disease or reflux-esophagitis, it is recommended to take 20 mg 1 time / day.
Duration of treatment is from 4 to 8 weeks. If necessary, the duration of treatment can be increased by another 8 weeks.
With maintenance therapy of gastroesophageal reflux disease (GERD), it is recommended to take 20 mg 1 time / day.
The duration of treatment depends on the patient's condition.
With non-erosive gastroesophageal reflux disease (NERD) without esophagitis, it is recommended to take 20 mg 1 time / day.

If after 4 weeks of treatment the symptoms do not disappear, an additional study of the patient should be carried out.

After relief of symptoms to prevent their subsequent occurrence, the drug should be taken orally 1 time / day on demand.

For the 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 in a dose up to 100 mg / day at a single dose or 60 mg 2 times / day. For some patients, fractional dosing of the drug is preferred. Treatment should continue as clinical necessity. In some patients with Zollinger-Alison syndrome, the duration of treatment with rabeprazole was up to 1 year.
To eradicate Helicobacter pylori it is recommended to take 20 mg 2 times / day according to a certain scheme with the appropriate combination of antibiotics.Duration of treatment is 7 days.

Correction of the dose in patients with renal insufficiency is not required.

In patients with mild to moderate hepatic insufficiency, the concentration of rabeprazole in the blood is usually higher than in healthy patients.
Care should be taken when administering the drug Rabinet ® to patients with severe hepatic insufficiency .
Correction of dose in elderly patients is not required.

The safety and efficacy of 20 mg rabeprazole sodium for short-term (up to 8 weeks) treatment of GERD in children aged 12 years or more is confirmed by extrapolation of the results of adequate and well-controlled studies that support the efficacy of rabeprazole sodium for adults and safety studies and pharmacokinetics for pediatric patients.
The recommended dose for children aged 12 years and over is 20 mg 1 time / day for up to 8 weeks.
The safety and efficacy of rabeprazole sodium for the treatment of GERD in children under the age of 12 years has not been established.

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

SIDE EFFECT

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 of a transient nature.
When using rabeprazole in clinical trials, the following side effects were noted.

From the nervous system: headache, dizziness.

On the part of the digestive system: abdominal pain, diarrhea, flatulence, constipation, dry mouth.

Other: rash, peripheral edema.

During the post-marketing use of the drug, the following side effects were reported.

From the digestive system: increased activity of liver enzymes;
rarely - hepatitis, jaundice. Patients with cirrhosis of the liver rarely reported the development of hepatic encephalopathy.
From the hemopoietic system: rarely - thrombocytopenia, neutropenia, leukopenia.

From the musculoskeletal system: rarely - myalgia, arthralgia.

Allergic reactions: rarely - bullous eruptions, hives, acute systemic allergic reactions;
very rarely - erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.
Other: rarely - hypomagnesemia;
very rarely - the development of interstitial nephritis, gynecomastia.
Changes in other laboratory parameters during the use of rabeprazole sodium were not observed.

According to post-marketing surveillance data, an increase in the risk of fractures is possible with the intake of proton pump inhibitors.

CONTRAINDICATIONS

- deficiency of sugar / isomaltase, fructose intolerance, glucose-galactose malabsorption syndrome;

- Pregnancy;

- the period of breastfeeding;

- age up to 12 years;

- hypersensitivity to rabeprazole, substituted benzimidazoles or to the auxiliary components of the drug.

With caution: should prescribe the drug in childhood, with renal failure severe.

PREGNANCY AND LACTATION

There are no data on the safety of rabeprazole during pregnancy.
Studies of reproductive performance in rats and rabbits showed no signs of impaired fertility or fetal developmental defects caused by rabeprazole; However, in rats, the drug penetrates small amounts through the placental barrier. The drug Rabiet ® should not be used during pregnancy, except when the expected positive effect for the mother exceeds 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 is found in the milk of lactating rats, so the drug Rabiet ® should not be given to women during breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER

Caution should be given to patients with severe renal insufficiency.

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

It is advisable to use caution at the first appointment of the drug rabeprazole to patients with severe impairment of liver function.

APPLICATION FOR CHILDREN

Contraindicated in children under the age of 12 years.

The safety and efficacy of 20 mg rabeprazole sodium for short-term (up to 8 weeks) treatment of GERD in children aged 12 years or more is confirmed by extrapolation of the results of adequate and well-controlled studies that support the efficacy of rabeprazole sodium for adults and safety studies and pharmacokinetics for pediatric patients.
The recommended dose for children aged 12 years and over is 20 mg 1 time / day for up to 8 weeks.
The safety and efficacy of rabeprazole sodium for the treatment of GERD in children under the age of 12 years has not been established.

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

APPLICATION IN ELDERLY PATIENTS

Dose adjustments in elderly patients are not required.

SPECIAL INSTRUCTIONS

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

In a special study in patients with mild or moderate liver function abnormalities, there was no significant difference in the frequency of side effects of rabeprazole from that in the healthy and well-chosen individuals, but nevertheless, caution should be exercised when first prescribing rabeprazole to patients with severe impairment of function liver.

Patients with impaired renal or hepatic function are not required to adjust the dose of rabeprazole.
AUC of rabeprazole sodium in patients with severe impairment of liver function is approximately 2 times higher than in healthy patients.
Hypomagnesemia

In the treatment of proton pump inhibitors for at least 3 months in rare cases, cases of symptomatic or asymptomatic hypomagnesemia were noted.
In most cases, these reports were received one year after the therapy. Serious side effects were tetany, arrhythmia, convulsions. Most patients required the treatment of hypomagnesemia, including the replacement of magnesium and the abolition of proton pump inhibitors. In patients who will receive long-term treatment, or take proton pump inhibitors with drugs such as digoxin, or drugs that can cause hypomagnesemia (eg diuretics), you should monitor the magnesium concentration before starting treatment with proton pump inhibitors and during treatment.
It is not necessary to take other agents that reduce acidity simultaneously with the drug Rabiet ® , for example, blockers of histamine H2-receptors or inhibitors of the proton pump.

Fractures of bones

According to observational studies, it can be assumed that therapy with proton pump inhibitors can lead to an increased risk of osteoporotic 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). Under high should be understood as doses exceeding those recommended in the instructions.
Concurrent use with methotrexate

According to the literature, the simultaneous use of proton pump inhibitors with methotrexate (especially in high doses) can lead to an increase in the concentration of methotrexate and / or its metabolite, hydroxymototrexate, and prolong the time of its removal, which may lead to the toxicity of methotrexate.
If methotrexate is needed in high doses, the possibility of a temporary cessation of therapy with proton pump inhibitors may be considered.
Clostridium difficile

Treatment with proton pump inhibitors may lead to an increased risk of gastrointestinal infections such as infections caused by Clostridium difficile.
Impact on the ability to drive vehicles and mechanisms

Based on the features of the pharmacodynamics of rabeprazole and profile of adverse effects it is unlikely that the drug has an effect on the ability to drive vehicles and management mechanisms. However, in case of drowsiness should avoid these activities.
OVERDOSE

Data on intentional or accidental overdose is minimal. rabeprazole there were no cases of severe overdose.
Treatment: symptomatic and maintenance therapy.
The specific antidote for rabeprazole is unknown. Rabeprazole binds well to plasma proteins so poorly displayed during dialysis.
DRUG INTERACTION

Cytochrome system 450
sodium rabeprazole, as well as other proton pump inhibitors, is metabolized with participation of cytochrome P450 (CYP450) in the liver. In in vitro studies on human liver microsomes, it was shown that sodium rabeprazole metabolized isozymes CYP2C19 and CYP3A4.
Studies in healthy volunteers have shown that sodium rabeprazole has pharmacokinetic or clinically significant interactions with drugs that are metabolized system cytochrome P450 - warfarin, phenytoin, theophylline and diazepam (whether as diazepam occurs metabolism in patients strongly or weakly).
Study of combination therapy with antibacterial drugs was carried out. In this four-way study involved 16 healthy volunteers who received 20 mg rabeprazole, 1000 mg amoxycillin 500 mg clarithromycin, or a combination of these three preparations (CANCER - rabeprazole, amoxicillin, clarithromycin). Indicators AUC and Cmax for clarithromycin and amoxicillin were similar when compared to combined therapy with monotherapy. Indicators AUC and C max for rabeprazole increased by 11% and 34% respectively, while for a 14-hydroxyclarithromycin (the active metabolite of clarithromycin) AUC and C maxincreased by 42% and 46% respectively for the combination therapy versus monotherapy. This increase in performance and the impact of rabeprazole clarithromycin was found to be clinically significant.
Interaction due to inhibition of gastric juice secretion
Rabeprazole sodium under sustainable and long-lasting inhibition of gastric acid secretion. Thus, there may be an interaction with substances for which absorption is independent of pH. Together with the admission rabeprazole sodium ketoconazole absorption is reduced by 30%, digoxin absorption is increased by 22%. Consequently, for some patients, observation should be conducted to solve the problem of the need to dose adjustment while the use of sodium rabeprazole with ketoconazole, digoxin or other drugs for which the absorption is dependent on pH.
atazanavir
When simultaneous administration of atazanavir 300 mg / 100 mg ritonavir with omeprazole (40 mg 1 time / day) or atazanavir 400 mg lansoprazole (60 mg 1 time / day) to healthy volunteers showed significant lowering effects of atazanavir. Absorption atazanavir depends on pH. While the simultaneous reception rabeprasol not studied, similar results are also expected for proton pump inhibitors. Thus, it is not recommended simultaneous reception of atazanavir with proton pump inhibitors, including rabeprazole.
Antacids
In clinical studies antacid used in conjunction with sodium rabeprazole. Clinically significant interaction rabeprazole sodium with aluminum hydroxide gel or magnesium hydroxide was not observed.
meal
In a clinical study during the reception with the depleted sodium rabeprazole fats clinically significant interaction with food was observed. Receiving sodium rabeprazole simultaneously with fat rich food may slow the absorption of rabeprazole up to 4 hours or more, but the C max does not change, and AUC.
Cyclosporin
experiments in vitro using human liver microsomes showed that cyclosporin inhibits metabolism rabeprazole with IC 50 62 micromoles, i.e. at a concentration of 50 times the C MAX for healthy volunteers after 20 days of application of rabeprazole in a dose of 20 mg. The degree of inhibition is similar to that of omeprazole for equivalent concentrations.
methotrexate
According to reports of adverse events, according to the published pharmacokinetic studies and retrospective analysis suggests that simultaneous reception of proton pump inhibitors and methotrexate (particularly in high dosage) may lead to increased concentrations of methotrexate and / or its metabolite gidroksimetotreksata and prolong the time of its removal . However, special studies of drug interactions with methotrexate proton pump inhibitors have been conducted.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The preparation should be stored in a dry place, protected from light and the reach of children at a temperature not higher than 25 ° C.
Shelf life - 2 years.
Do not use after the expiration date printed on the package.

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