Composition, form of production and packaging
The tablets covered with an enteric-soluble coating of light yellow color, rounded, biconvex, on one side marked with red ink "E243"; the color of the tablet on the cross-section is from white to almost white.
rabeprazole sodium 20 mg,
which corresponds to the content of rabeprazole 18.85 mg
Auxiliary substances: mannitol (mannitol) - 40 mg, magnesium oxide - 63 mg, hydroxypropylcellulose weakly substituted (giprolase) - 19.5 mg, hydroxypropyl cellulose (giprolose) - 3 mg, magnesium stearate - 1.5 mg, ethyl cellulose - 1 mg, hypromellose phthalate - 12 mg , diacetylated monoglyceride 1.2 mg, talc 1.13 mg, titanium dioxide (E171) 0.6 mg, iron oxide yellow 0.07 mg, carnauba wax 0.002 mg, red food alum A1 (white shellac, iron oxide red, carnauba wax, complex glycerol ester, ethanol dehydrated, 1-butanol).
7 pcs. - blisters of 2 layers of aluminum (1) - packs of cardboard.
7 pcs. - blisters of 2 layers of aluminum (2) - packs of cardboard.
14 pcs. - blisters of 2 layers of aluminum (1) - packs of cardboard.
14 pcs. - blisters of 2 layers of aluminum (2) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2016.
A drug that reduces the secretion of the glands of the stomach is an inhibitor of the proton pump.
Mechanism of action
Rabeprazole sodium belongs to the class of antisecretory substances, derivatives of benzimidazole. Rabeprazole sodium suppresses the secretion of gastric juice by specifically inhibiting 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.
After oral administration of 20 mg of rabeprazole sodium, the antisecretory effect develops within an hour. The 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 higher than predicted by T 1/2 (approximately one hour). This effect can be explained by 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 three days of taking rabeprazole sodium. At the termination of reception secretory activity is restored within 1-2 days.
Effect on the level of gastrin in plasma
In clinical trials, patients took 10 or 20 mg of rabeprazole sodium daily for up to 43 months. The level of gastrin in the 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 enterochromafin-like cells
In the study of human gastric biopsy specimens from the antrum and gastric floor area, 500 patients receiving either rabeprazole sodium or a reference preparation for 8 weeks, stable changes in the morphological structure of enterochroma- phin-like cells, the degree of gastritis, the frequency of atrophic gastritis, intestinal metaplasia or the spread of Helicobacter infection pylori 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 of omeprazole (20 mg / kg). No case of adenomatous changes or carcinoid tumors observed in rats was recorded.
The systemic effects of rabeprazole sodium in relation to the central nervous system, cardiovascular or respiratory systems are not currently detected. It has been shown that sodium rapeprasol, when administered orally at a dose of 20 mg for 2 weeks, has no effect on thyroid function, carbohydrate metabolism, parathyroid hormone levels in the blood, and on the level of cortisol, estrogens, testosterone, prolactin, glucagon, FSH, LH, renin, aldosterone and growth hormone.
Rabeprazole is rapidly absorbed from the intestine, and its peak plasma concentrations are reached approximately 3.5 hours after taking a 20 mg dose. The change in peak plasma concentrations (C max) and the values вЂ‹вЂ‹of AUB rabeprazole are linear in the dose range of 10 to 40 mg. Absolute bioavailability after oral administration of 20 mg (compared with intravenous administration) is about 52%. In addition, bioavailability does not change with multiple administration of rabeprazole. In healthy volunteers, the T 1/2 period from the plasma is about 1 hour (varying from 0.7 to 1.5 hours), and the total clearance is 3.8 ml / min / kg.
In patients with chronic liver disease, the AUC is doubled compared to healthy volunteers, which indicates a decrease in the metabolism of the first passage, and T 1/2from the plasma is increased by 2-3 times. Neither the time of taking the drug during the day, nor antacids affect the absorption of rabeprazole. Admission of the preparation with fatty food slows the absorption of rabeprazole by 4 hours or more, however neither the C max nor the degree of absorption is changed.
In humans, the degree of binding of rabeprazole to plasma proteins is about 97%.
Metabolism and excretion
In healthy people. After taking a single oral dose of 20 mg of 14 C-labeled rabeprazole sodium, no unchanged drug was found in the urine. About 90% of rabeprazole is excreted in the urine 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 with feces. The total excretion is 99.8%. These data indicate a slight excretion of metabolites of rabeprazole sodium with bile. The main metabolite is thioester (M1). The only active metabolite is desmethyl (M3), but it was observed in low concentration only in one participant in the study after taking 80 mg of rabeprazole.
Terminal stage of renal failure. In patients with stable renal insufficiency in the terminal stage, which require maintenance hemodialysis (creatinine clearance <5ml / min / 1.73m 2 ), removal of rabeprazole sodium is similar to that of healthy volunteers. AUC and Cmax 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 kidney disease requiring hemodialysis was approximately twice that of healthy volunteers.
Chronic compensated cirrhosis. Patients with chronic compensated cirrhosis transfer rabeprazole sodium at a dose of 20 mg 1 time per day, although 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 down. After 7 days of taking rabeprazole 20 mg per day in elderly people, the AUC was approximately twice as large, and C max was increased by 60% compared to young healthy volunteers. However, there were no signs of cumulation of rabeprazole.
CYP2C19 polymorphism. In patients with delayed metabolism of CYP2C19 after 7 days of taking rabeprazole at a dose of 20 mg per day, the AUC increases 1.9-fold, and Cmax 1.6-fold compared with the same parameters in "fast metabolizers," while Cmax increases by 40 %.
- Stomach ulcer in the phase of exacerbation and an anastomosis ulcer;
- Duodenal ulcer in the phase of exacerbation;
- 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 antibiotic therapy for the eradication of Helicobacter pylori in patients with peptic ulcer.
The tablets of Pariet В® should be swallowed whole, without 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 the anastomosis, it is recommended to take 20 mg 1 time per 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 per 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 (GERD) or reflux esophagitis, it is recommended to take 20 mg 1 time per 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 per 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 per 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 treatment of Zollinger-Elison 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 of up to 100 mg once a day or 60 mg 2 times a day. For some patients, fractional dosing of the drug is preferred. Treatment should continue as clinical need arises. In some patients with Zollinger-Alison syndrome, the duration of treatment with rabeprazole was up to 1 year.
For eradication of Helicobacter pylori, it is recommended to take 20 mg orally 2 times a day in a certain scheme with the appropriate combination of antibiotics.Duration of treatment is 7 days.
Patients with renal and hepatic insufficiency
Dose adjustments in patients with renal insufficiency are not required.
In patients with mild and moderate hepatic insufficiency, the concentration of rabeprazole in the blood is usually higher than in healthy patients.
Care should be taken when administering Pariete В® to patients with severe hepatic impairment.
Correction of the dose 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.
Based on the experience of clinical studies, it can be concluded that Pariet В® is usually well tolerated by patients. Side effects are generally mild or moderate and of a transient nature.
When taking Pariete В® in clinical trials, the following side effects were noted: headache, abdominal pain, diarrhea, flatulence, constipation, dry mouth, dizziness, rash, peripheral edema.
Undesirable reactions are systematized relative to each of the organ systems using the following classification of frequency: very often (? 1/10), often (? 1/100, <1/10), infrequently (? 1/1000, <1/100), rarely (? 1/10 000, <1/1000), very rarely (<1/10 000), including isolated cases.
Disorders from the immune system: rarely - acute systemic allergic reactions.
Violations from the blood and lymphatic system: rarely - thrombocytopenia, neutropenia, leukopenia.
Disorders from the metabolism and nutrition: rarely - hypomagnesemia.
Disorders from the hepatobiliary system: increased activity of hepatic enzymes, rarely - hepatitis, jaundice, hepatic encephalopathy.
Disorders from the kidneys and urinary tract: very rarely - interstitial nephritis.
Disturbances from the skin and subcutaneous tissues: rarely - bullous rashes, hives, very rarely - erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.
Disturbances from the musculoskeletal system: rarely - myalgia, arthralgia.
Disorders from the reproductive system: very rarely - gynecomastia.
Changes in other laboratory parameters during the use of rabeprazole sodium were not observed. According to the data of the postmarketing observations when taking proton pump inhibitors (PPI), it is possible to increase the risk of fractures.
- lactation period;
- children's age till 12 years;
- hypersensitivity to rabeprazole, substituted benzimidazoles or to the auxiliary components of the drug
Use with caution in patients with severe renal insufficiency, in childhood.
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 impairment
fertility or fetal developmental defects caused by rabeprazole; However, in rats in small quantities, the drug penetrates through the placental barrier. Pariet В® should not be used during pregnancy, except when the expected positive effect for the mother exceeds the possible harm to the fetus.
It is not known whether rabeprazole is excreted in breast milk. Appropriate studies in lactating women were not conducted. However, rabeprazole is found in the milk of lactating rats, and therefore Pariet В® can not be administered to lactating women.
APPLICATION FOR FUNCTIONS OF THE LIVER
Patients with renal insufficiency do not need dose adjustment.
Use with caution in patients with severe renal insufficiency.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Patients with liver failure are not required to adjust the dose.
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 Pariete В® to patients with severe hepatic insufficiency.
APPLICATION FOR CHILDREN
Pariet В® is not recommended for children under 12 years of age, since there is currently no experience of its use in pediatric practice.
APPLICATION IN ELDERLY PATIENTS
Older patients do not need a dose adjustment.
The patient's response to rabeprazole sodium therapy does not exclude the presence of malignant neoplasms in the stomach.
Tablets of Pariet В® can not be chewed or grinded. Tablets should be swallowed whole. It has been established that neither the time of day nor the intake of food affects the activity of rabeprazole sodium.
In a special study in patients with mild or moderate liver function abnormalities, there was no significant difference in the frequency of the adverse effects of ParietoВ® from that of the healthy individuals selected by sex and age, but in spite of this, it is advisable to use caution at the first appointment of Pariet В® to patients with severe impairment of liver function. AUC of rabeprazole sodium in patients with severe impaired liver function is approximately twice as high as in healthy patients.
Patients with impaired renal or hepatic function are not required to adjust the dose of Pariet В® .
In the treatment of proton pump inhibitors (PPIs) 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 and convulsions. Most patients required treatment of hypomagnesemia, including the replacement of magnesium and the abolition of proton pump inhibitor therapy.
In patients who will receive long-term treatment or who take PPI with drugs such as digoxin or drugs that can cause hypomagnesemia (eg diuretics), health professionals should monitor the magnesium concentration before starting treatment with proton pump inhibitors and during treatment.
Patients should not take other agents that reduce acidity concomitantly with Pariete В® , for example, H 2 -receptor blockers or PPI.
According to observational studies, it can be assumed that IPP therapy may lead to an increased risk of osteoporotic fractures of the hip, wrist, or spine. The risk of fractures was increased in patients who received high doses of PPI for a long time (a year or more).
The simultaneous use of rabeprazole with methotrexate
According to the literature, simultaneous IPP with methotrexate (particularly in high dosage) may lead to increased concentrations of methotrexate and / or a metabolite thereof, and enlarge gidroksimetotreksata period T 1/2 , which can lead to the manifestation of toxicity of methotrexate. If necessary, use of high doses of methotrexate may be considered temporary cessation therapy IPP.
Therapy PPI may lead to increase risk of gastrointestinal infections such as Clostridium difficile.
Impact on the ability to drive vehicles and manage mechanisms
Based on the characteristics pharmacodynamic profile is rabeprazole and undesirable effects, it is unlikely that Pariet В® affects the ability to drive and operate machinery. However, in case of drowsiness should avoid these activities.
Symptoms : evidence of intentional or accidental overdose is minimal. Rabeprazole there were no cases of severe overdose.
Treatment: specific antidote for the drug Pariet В® unknown. Rabeprazole well bound to plasma proteins, and therefore poorly displayed during dialysis. In case of overdose should be carried out is symptomatic and supportive treatment.
System cytochrome P450
sodium rabeprazole, as well as other proton pump inhibitors (PPI), is metabolized with the 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 or has no clinically significant pharmacokinetic interactions with drugs that are metabolized by the cytochrome P450 system - warfarin, phenytoin, theophylline and diazepam (regardless of whether patients metabolize diazepam strongly or weakly).
Study of combination therapy with antibacterial drugs was carried out. In this four-way crossover 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 C max 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, and for 14-hydroxy-clarithromycin (the active metabolite of clarithromycin) AUC and C maxincreased by 42% and 46%, respectively, for the combination therapy versus monotherapy. This increase in impact indicators for rabeprazole, and 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% and the absorption of digoxin is increased by 22%. Consequently, for some patients, observation should be conducted to solve the problem of the need to adjust dosages while taking rabeprazole sodium with ketoconazole, digoxin or other medicinal preparations, for which the absorption is dependent on pH.
When simultaneous administration of atazanavir 300 mg / 100 mg ritonavir with omeprazole (40 mg once a day 1) or atazanavir 400 mg lansoprazole (60 mg 1 time per day) to healthy volunteers showed significant lowering effects of atazanavir. Absorption atazanavir depends on pH. Although simultaneous with rabeprazole was not studied, similar results are also expected for other STIs. Thus, it is not recommended simultaneous reception of atazanavir with proton pump inhibitors, including rabeprazole.
In clinical studies, antacid agents used jointly with sodium rabeprazole. Clinically relevant interaction of rabeprazole sodium with aluminum hydroxide gel or magnesium hydroxide were observed.
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 and AUC are not changed.
Experiments in vitro c using human liver microsomes showed that cyclosporin inhibits metabolism rabeprazole with IC 50 62 .mu.mol, t. E. At a concentration 50 times higher than the C max for healthy volunteers after 20 days of 20 mg of rabeprazole. The degree of inhibition is similar to that of omeprazole for equivalent concentrations.
According to reports of adverse events, according to the published pharmacokinetic studies and retrospective analysis suggests that simultaneous reception of IPP and methotrexate (particularly in high dosage) may lead to increased concentrations of methotrexate and / or a metabolite thereof, and enlarge gidroksimetotreksata T 1/2 .However, special studies of drug interactions with methotrexate IPP was conducted.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored in reach of children at a temperature not higher than 25 В° C; Do not freeze. Shelf life - 2 years. Do not use after the expiration date.