Pariyet

General characteristics. Structure:

Active agent: рабепразол sodium, 20 mg that in recalculation corresponds to 18,85 mg of a rabeprazol, respectively.

Excipients: a mannitol (Mannitolum) - 40,0 mg, magnesium oxide - 63,0 mg, hydroxypropyl cellulose slabozameshchenny (hypro rod) - 19,5 mg, hydroxypropyl cellulose (hypro rod) - 3,0 mg, magnesium stearate - 1,5 mg, ethyl cellulose - 1,0 mg, gipromelloza phthalate - 12,0 mg, a diacetylized monoglyceride - 1,2 mg, talc - 1,13 mg, titanium dioxide (E171) - 0,6 mg, ferrous oxide yellow - 0,07 mg, karnaubsky wax - 0,025 mg, blackened food red A1 (white shellac, ferrous oxide the red, karnaubsky wax, ester of glyceric acid, ethanol dehydrated 1 Butanol)).

The description / Light yellow biconvex tablets of rounded shape, coated, on one party marking by red E243 ink. Color of a tablet on cross section from white till almost white color. 

Pharmacological properties:

Pharmacodynamics.

Action mechanism. Rabeprazol of sodium belongs to the class of the anti-secretory substances derivative of benzimidazole. Rabeprazol of sodium suppresses secretion of a gastric juice by specific inhibition of H+/K+ of Atfaza on the secretory surface of covering cells of a stomach. H+/K + Atfaza represents a proteinaceous complex which functions as the proton pomp, thus, рабепразол sodium is inhibitor of a proton pomp in a stomach and blocks a final stage of products of acid. This effect is dozozavisimy and leads to suppression both the basal, and stimulated secretion of acid irrespective of an irritant.

Rabeprazol of sodium has no anticholinergic properties.

Anti-secretory action. After oral administration of 20 mg of a rabeprazol of sodium the anti-secretory effect develops within an hour. The inhibition of the basal and stimulated secretion of acid in 23 hours after reception of the first dose of a rabeprazol of sodium makes 69% and 82% respectively, and proceeds till 48 o'clock. Such duration of pharmakodinamichesky action much more exceeds predictable on an elimination half-life (about one hour). This effect can be explained with long linkng of medicinal substance with H+/K+ by Atfaza of covering cells of a stomach. The size of an inhibiting effect of a rabeprazol of sodium on secretion of acid reaches the plateau after three days of reception of a rabeprazol of sodium. At the reception termination, secretory activity is recovered within 1-2 days.

Influence on gastrin level in plasma. During clinical trials patients accepted 10 or 20 mg of a rabeprazol of sodium daily lasting treatment up to 43 months. Gastrin level in plasma was increased the first 2-8 weeks that reflects an inhibiting effect on acid secretion. Concentration of gastrin was returned to initial level usually within 1-2 weeks after the treatment termination.

Influence on enterokhromafinno-like cells. At a research of samples of a biopsy of a stomach of the person from area of an antrum and a greater cul-de-sac of 500 patients receiving рабепразол sodium or comparison drug within 8 weeks, steady changes in morphological structure of enterokhromafinno-like cells, gastritis degree of manifestation, frequency of atrophic gastritis, intestinal metaplasia or spread of an infection of Helicobacter pylori were not found. In a research with participation more than 400 patients receiving рабепразол sodium (10 mg/day or 20 mg/day) duration till 1 year, the frequency of a hyperplasia was low and comparable with that for an omeprazol (20 mg/kg). Any case of the adenomatous changes or carcinoid tumors observed at rats was not registered.

Other effects. System effects of a rabeprazol of sodium concerning the central nervous system, cordial vascular or respiratory systems are at the moment not found. It was shown what рабепразол sodium at oral administration in a dose of 20 mg within 2 weeks does not exert impact on function of a thyroid gland, carbohydrate metabolism, level of parathyroid hormone in blood, and also on the level of cortisol, estrogen, testosterone, prolactin, a glucagon, follicle-stimulating hormone (FSG), luteinizing hormone (LH), a renin, Aldosteronum and somatotropic hormone.

Pharmacokinetics.

Absorption. Rabeprazol is quickly absorbed from intestines, and its peak concentration in plasma are reached approximately in 3,5 h after reception of a dose in 20 mg. Change of peak concentration in plasma (Cmax) and values of the area under a curve "concentration time" (AUC) of a rabeprazol have linear character in the range of doses from 10 to 40 mg. Absolute bioavailability after oral administration of 20 mg (in comparison with intravenous administration) makes about 52%. Besides, bioavailability does not change at multiple dose of a rabeprazol. At healthy volunteers plasma elimination half-life makes about 1 h (varying from 0,7 to 1,5 h), and the total clearance makes 3,8 ml/min. At patients with chronic damage of a liver of AUC it is doubled in comparison with healthy volunteers that demonstrates decrease in metabolism of the first passing, and plasma elimination half-life is increased by 2-3 times. Neither time of administration of drug within a day, nor antacids influence absorption of a rabeprazol. Administration of drug with greasy food slows down absorption of a rabeprazol for 4 hours and more, however neither Cmax, nor extent of absorption change.

Distribution. At the person extent of linkng of a rabeprazol with proteins of plasma makes about 97%.

Metabolism and removal.

At healthy people After reception of a single peroral dose of 20 mg of a 14C-mechenny rabeprazol of sodium of not changed drug in urine it was not found. About 90% of a rabeprazol are removed with urine mainly in the form of two metabolites: a conjugate of mercapturic acid (M5) and carboxylic acid (M6), and also in the form of two unknown metabolites revealed during the toxicological analysis. The rest of the accepted rabeprazol of sodium is removed with a stake. Total removal makes 99,8%. These data confirm small removal of metabolites of a rabeprazol of sodium with bile. The main metabolite is monothioester (M1). The only active metabolite is desmetit (M3), however it was observed in low concentration only at one participant of a research after reception of 80 mg of a rabeprazol.

End-stage of a renal failure. At patients with a stable renal failure in an end-stage for whom the supporting hemodialysis is necessary (clearance of creatinine <5ml/min/1,73m2), removal of a rabeprazol of sodium is similar to that for healthy volunteers. AUC and Cmax at these patients were about 35% lower, than at healthy volunteers. The elimination half-life of a rabeprazol averaged 0,82 h at healthy volunteers, patients have 0,95 h during a hemodialysis and 3,6 h after a hemodialysis. The clearance of drug at patients with diseases of the kidneys needing a hemodialysis was approximately twice higher, than at healthy volunteers.

The chronic compensated cirrhosis. Patients with the chronic compensated cirrhosis transfer рабепразол sodium in a dose 20 mg once a day though AUC is doubled and Cmax is increased by 50% in comparison with healthy volunteers of the corresponding floor.

Elderly patients. At elderly patients elimination of a rabeprazol is slowed a little down. After 7 days of reception of a rabeprazol on 20 mg a day at the elderly persons AUC was approximately twice more, and Cmax is raised for 60% in comparison with young healthy volunteers. However, signs of cumulation of a rabeprazol were not noted.

CYP2C19 polymorphism. At patients with the slowed-down metabolism of CYP2C19 after 7 days of reception of a rabeprazol in a dose of 20 mg in days of AUC the elimination half-life by 1,6 times in comparison with the same parameters at "bystry metabolizator" while Cmax increases by 40% increases by 1,9 times, and.

Indications to use:

- A peptic ulcer of a stomach in a stage of an aggravation and an anastomosis ulcer;

- A peptic ulcer of a duodenum in an aggravation stage;

- Erosive and ulcer gastroesophageal reflux disease or reflux esophagitis;

- Maintenance therapy of a gastroesophageal reflux disease;

- Not erosive gastroesophageal reflux disease;

- Zollingera-Ellison's syndrome and others a state, characterized by pathological hypersecretion;

- In a combination with the corresponding antibacterial therapy for Helicobacter pylori eradikation at patients with a peptic ulcer. 

Route of administration and doses:

Tablets of drug of Pariyet cannot be chewed or crushed. It is necessary to swallow of tablets entirely. It is established that neither time of day, nor meal influence activity of a rabeprazol of sodium.

At a peptic ulcer of a stomach in a stage of an aggravation and an ulcer of an anastomosis about 20 mg are recommended to accept inside once a day. Usually treatment comes after 6 weeks of therapy, however in certain cases duration of treatment can be increased for 6 weeks.

At a peptic ulcer of a duodenum in a stage of an aggravation about 20 mg are recommended to accept inside once a day. Duration of treatment makes from 2 to 4 weeks. In case of need duration of treatment can be increased for 4 weeks.

At treatment of an erosive gastroesophageal reflux disease (GERB) or the reflux an esophagitis is recommended to accept inside on 20 mg once a day. Duration of treatment makes from 4 to 8 weeks. In case of need duration of treatment can be increased for 8 weeks.

At a maintenance therapy of a gastroesophageal reflux disease (GERB) about 20 mg are recommended to accept inside once a day. Duration of treatment depends on a condition of the patient.

At not erosive gastroesophageal reflux disease (NERB) without esophagitis about 20 mg are recommended to accept inside once a day. If after four weeks of treatment symptoms do not disappear, it is necessary to conduct an additional research of the patient. After stopping of symptoms for the prevention of their subsequent emergence it is necessary to accept drug inside once a day on demand.

For the treatment of a syndrome of Zollingera-Elison and other states which are characterized by pathological hypersecretion, the dose is selected individually. An initial dose – 60 mg a day, then raise a dose and appoint drug in a dose to 100 mg a day at a single dose or on 60 mg twice a day.

For some patients the fractional drug dosing is preferable. Treatment has to continue in process of clinical need. Some patients with Zollingera-Elison's syndrome have treatment duration rabeprazoly made up to one year. For an eradikation of Helicobacter pylori about 20 mg 2 times a day according to a certain scheme with the corresponding combination of antibiotics are recommended to accept inside. Duration of treatment makes 7 days.

Patients with a renal and liver failure. Dose adjustment is not required to patients with a renal failure. At patients with easy and moderate degree of a liver failure concentration of a rabeprazol in blood is usually higher, than at healthy patients. At purpose of drug of Pariyet patients should be careful with heavy degree of a liver failure.

Elderly patients. Dose adjustment is not required.

Children. Safety and efficiency of a rabeprazol of sodium of 20 mg for short-term (up to 8 weeks) treatments of GERB at children at the age of 12 years is also more confirmed with extrapolation of results of the adequate and well controlled researches supporting efficiency of a rabeprazol of sodium for adults and researches of safety and pharmacokinetics for patients of children's age. The recommended dose for children at the age of 12 years and more makes 20 mg lasting up to 8 weeks once a day.

Safety and efficiency of a rabeprazol of sodium for treatment of GERB at children are aged younger than 12 years is not established. Safety and efficiency of a rabeprazol of sodium for use according to other indications is not established for patients of children's age.

Features of use:

The response of the patient to therapy rabeprazoly sodium does not exclude existence of malignant new growths in a stomach.

Tablets of drug of Pariyet cannot be chewed or crushed. It is necessary to swallow of tablets entirely. It is established that neither time of day, nor meal influence activity of a rabeprazol of sodium.

In a special research at patients with easy or moderate abnormal liver functions significant difference of frequency of side effects of drug of Pariyet from that at the healthy faces which are picked up for gender and age, but, despite it was not revealed, it is recommended to be careful at the first purpose of drug of Pariyet to patients with heavy abnormal liver functions. AUC of a rabeprazol of sodium at patients with a heavy abnormal liver function is approximately twice higher, than at healthy patients. Or a liver correction of a dose of drug of Pariyet is not required to patients with renal failures.

Hypomagnesiemia. At treatment inhibitors of a proton pomp for at least 3 months in rare instances noted cases of a symptomatic or symptomless hypomagnesiemia. In most cases these messages arrived in a year after performing therapy. The tetany, arrhythmia and spasms were serious by-effects. Most of patients needed treatment of the hypomagnesiemia including substitution of magnesium and cancellation of therapy of inhibitors of a proton pomp. At patients who will receive prolonged treatment or who accept inhibitors of a proton pomp with drugs, such as digoxin or drugs which can cause a hypomagnesiemia (for example diuretics) health workers have to control concentration of magnesium prior to treatment by inhibitors of a proton pomp and during treatment.

Patients should not accept other means reducing acidity, for example blockers of H2 receptors or inhibitors of a proton pomp along with Pariyet's drug.

Fractures of bones. According to data of the observation researches it is possible to assume that therapy by the inhibitors of a proton pomp (IPP) can lead to increase of risk of the fractures of a hip, wrist or backbone connected with osteoporosis. The risk of changes was increased at the patients receiving high doses of IPP year and more is long ().

Simultaneous use of a rabeprazol with a methotrexate. According to literary data, the concomitant use of IPP with a methotrexate (first of all in high doses), can lead to increase in concentration of a methotrexate and/or its metabolite of a hydroxymethotrexate and increase an elimination half-life that can lead to manifestation of toxicity of a methotrexate. In need of use of high doses of a methotrexate, the possibility of the temporary termination of therapy of IPP can be considered.

Clostridium difficile. Therapy of IPP can lead to increase of risk of gastrointestinal infections, such as Clostridium difficile.

Influence on driving of the car and work with the equipment. Proceeding from features of a pharmacodynamics of a rabeprazol and its profile of undesirable effects, it is improbable that Pariyet exerts impact on ability to drive the car and to work with the equipment. However in case of drowsiness it is necessary to avoid these types of activity.

 

Side effects:

As a matter of experience clinical trials, it is possible to draw a conclusion that Pariyetobychno is well had by patients. Side effects in general poorly expressed or moderated also have passing character.

At administration of drug of Pariyet during clinical trials the following side effects were noted: a headache, an abdominal pain, diarrhea, a meteorism, a lock, dryness in a mouth, dizziness, rash, peripheral hypostasis.

Undesirable reactions are systematized concerning each of systems of bodies with use of the following classification of frequency of occurrence:

- very frequent (≥1/10);

- frequent (≥1/100, <1/10);

- infrequent (≥1/1000, <1/100);

- rare (≥1/10000, <1/1000);

- very rare (<1/10000), including isolated cases.

Disturbances from immune system: seldom - acute system allergic reactions.

Disturbances from blood and lymphatic system: seldom - thrombocytopenia, a neutropenia, a leukopenia.

Disturbances from a metabolism and food: seldom - a hypomagnesiemia.

Disturbances from gepatobiliarny system: increase in activity of liver enzymes, is rare - hepatitis, jaundice, hepatic encephalopathy.

Disturbances from kidneys and urinary tract: very seldom - intersticial nephrite.

Disturbances from skin and hypodermic fabrics: seldom - violent rashes, urticaria, very seldom-multiformnaya an erythema, a toxic epidermal necrolysis, Stephens's syndrome - Johnson.

Disturbances from a musculoskeletal system: seldom - a mialgiya, an arthralgia.

Disturbances from reproductive system: very seldom - a gynecomastia.

Changes of other laboratory indicators during reception of a rabeprazol of sodium were not observed. According to data of posmarketingovy observations at reception of the inhibitors of a proton pomp (IPP) perhaps increase in risk of developing of fractures (see the section "Special Instructions"). 

Interaction with other medicines:

System of cytochrome 450.

Rabeprazol of sodium, as well as other inhibitors of a proton pomp (IPP), is metabolized with participation of system of P450 (CYP450) cytochrome in a liver. In the researches in vitro on microsomes of a liver of the person it was shown what рабепразол sodium is metabolized by isoenzymes of CYP2C19 and CYP3A4.

Researches on healthy volunteers showed what рабепразол sodium has no pharmacokinetic or clinically significant interactions with medicinal substances which it is metabolized by system of P450 cytochrome - warfarin, Phenytoinum, theophylline and diazepam (irrespective of whether patients metabolize diazepam strenuously or poorly).

The research of a combination therapy with antibacterial drugs was conducted. 16 healthy volunteers who received 20 mg of a rabeprazol, 1000 mg of amoxicillin, 500 mg of a klaritromitsin or a combination of these three drugs (CANCER - рабепразол, amoxicillin, кларитромицин) participated in this quadrilateral cross research. Indicators of AUC and Cmax for a klaritromitsin and amoxicillin were similar when comparing a combination therapy with monotherapy. Indicators of AUC and Cmax for a rabeprazol increased by 11% and 34%, respectively, and for 14-hydroxy-klaritromitsina (an active metabolite of a klaritromitsin) of AUC and Cmax increased by 42% and 46%, respectively, for a combination therapy in comparison with monotherapy. This increase in indicators of influence for a rabeprazol and a klaritromitsin was not recognized as clinically significant.

Interactions owing to inhibition of secretion of a gastric juice. Rabeprazol of sodium carries out steady and long suppression of secretion of a gastric juice. Thus, there can be an interaction to substances for which absorption depends on pH. At a concomitant use with rabeprazoly sodium absorption of a ketokonazol decreases by 30%, and absorption of digoxin increases by 22%. Therefore, for some patients observation for the solution of a question of need of correction of a dose at a concomitant use of a rabeprazol of sodium has to be made with ketokonazoly, digoxin or others medicinal drugs for which absorption depends on pH.

Atazanavir. At a concomitant use of an atazanavir of 300 mg / ритонавира 100 mg with omeprazoly (40 mg once a day) or from an atazanavir of 400 mg with lansoprazoly (60 mg once a day) healthy volunteers observed essential decrease in influence of an atazanavir. Absorption of an atazanavir depends on pH. Though the concomitant use with rabeprazoly was not studied, similar results are expected also for other inhibitors of the proton pump. Thus, the concomitant use of an atazanavir with inhibitors of the proton pump, including рабепразол is not recommended.

Antiacid means. In clinical trials antiacid substances were applied together with rabeprazoly sodium. Clinically significant interactions of a rabeprazol of sodium with gel of aluminum hydroxide or with magnesium hydroxide were not observed.

Meal. In clinical trial during reception of a rabeprazol of sodium with the food of clinically significant interactions which is grown poor by fats it was not observed. Reception of a rabeprazol of sodium along with the food enriched with fats can slow down absorption of a rabeprazol till 4 o'clock and more, however Cmax and AUC do not change.

Cyclosporine. Experiments of in vitro c use of microsomes of a liver of the person showed what рабепразол inhibits metabolism of cyclosporine from IC50 62 µmol, i.e. in concentration, by 50 times of the exceeding Cmax for healthy volunteers after 20 days of reception of 20 mg of a rabeprazol. Degree of inhibition is similar to that for an omeprazol for equivalent concentration.

Methotrexate. According to data of messages on the undesirable phenomena, data of the published pharmacokinetic researches and data of the retrospective analysis it is possible to assume that the concomitant use of IPP and a methotrexate (first of all in high doses), can lead to increase in concentration of a methotrexate and/or its metabolite of a hydroxymethotrexate and increase an elimination half-life. Nevertheless, special researches of medicinal interaction of a methotrexate with IPP were not conducted.

 

Contraindications:

- hypersensitivity to a rabeprazol, the replaced benzimidazoles or to auxiliary components of drug;

- pregnancy;

- lactation period;

- children's age up to 12 years.

With care:

- children's age;

- heavy renal failure. 

Overdose:

Symptoms.

Data on intended or accidental overdose are minimum. Cases of strong overdose rabeprazoly were not noted.

Treatment.

The specific antidote for Pariyet's drug is unknown. Rabeprazol well contacts proteins of plasma and therefore it is poorly removed at dialysis. At overdose it is necessary to carry out the symptomatic and supporting treatment.

Storage conditions:

At a temperature not above 25 °C in the place, unavailable to children. Not to freeze.

Issue conditions:

According to the recipe

Packaging:

The tablets covered with a kishechnorastvorimy cover of 20 mg. On 7 or 14 tablets in the blister from 2 layers of aluminum. On 1 or 2 blisters together with the instruction on a medical use in a cardboard pack.