Composition, form of production and packaging
Tablets covered with an enteric-soluble coat of orange-pink color, round, biconvex, with a facet.
1 tab.
rabeprazole sodium 10 mg,
which corresponds to the content of rabeprazole 9.42 mg
Excipients: mannitol (E421) - 18.5 mg, magnesium oxide light - 30 mg, giprolose - 2.625 mg, low-substituted giprolose - 12.75 mg, magnesium stearate - 1.125 mg.
Composition of the coating (tie layer): ethyl cellulose 0.44 mg, magnesium oxide light 0.61 mg.
The composition of the shell (enteric- soluble ): hypromellose phthalate - 6.3 mg, diacetylated monoglycerides - 0.64 mg, talc 0.59 mg, titanium dioxide (E171) 0.32 mg, iron oxide red oxide (E172) 0.017 mg.
14 pcs. - blisters (1) - packs of cardboard.
14 pcs. - blisters (2) - packs of cardboard.
The tablets covered with an enteric- soluble coat of brownish-yellow color, round, biconvex, with a facet.
1 tab.
rabeprazole sodium 20 mg,
which corresponds to the content of rabeprazole 18.85 mg
Excipients: mannitol (E421) - 37 mg, magnesium oxide light - 60 mg, giprolose - 5.25 mg, low-substituted giprolose - 25.5 mg, magnesium stearate - 2.25 mg.
The composition of the shell (tie layer): ethyl cellulose - 1.2 mg, magnesium oxide light - 1.65 mg.
The composition of the shell (enteric- soluble ): hypromellose phthalate - 13.8 mg, diacetylated monoglycerides - 1.4 mg, talc - 1.3 mg, titanium dioxide (E171) - 0.7 mg, ferric oxide yellow oxide (E172) - 0.08 mg.
14 pcs. - blisters (1) - packs of cardboard.
14 pcs. - blisters (2) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
PHARMACHOLOGIC EFFECT
Rabeprazole belongs to the class of antisecretory drugs, substituted benzimidazoles, which do not possess anticholinergic or antihistamine properties, and suppress gastric secretion by inhibiting the enzyme H + / K + -ATPase (proton pump). The effect of the drug depends on the dose and leads to suppression of basal and stimulated secretion of hydrochloric acid in the stomach, regardless of the stimulating factors. Studies in animals have shown that rabeprazole rapidly disappears from the plasma and the gastric mucosa. As a weak base, rabeprazole is rapidly absorbed in all dosages and accumulates in the acidic environment of the parietal cells of the stomach. Rabeprazole is converted into a sulfenamide form by protonation and then interacts with the available proton pump cysteine ​​molecules.
Antisecretory action: after taking 20 mg of rabeprazole, the antisecretory effect begins to develop within 1 hour, reaching a maximum after 2-4 hours. The suppression of basal and food-stimulated hydrochloric acid secretion in the stomach after 23 hours after the first dose of rabeprazole is 69% and 82% , respectively, and lasts up to 48 hours. The inhibitory effect of rabeprazole on the secretion of hydrochloric acid when taking repeated doses increases slightly, reaching an equilibrium state after 3 days. After the drug is discontinued, the secretory activity of the stomach is restored after 2-3 days.
In vitro It was found that rabeprazole has a bactericidal action against Helicobacter pylori . Eradication of Helicobacter pylori with rabeprazole and antimicrobial agents leads to a high degree of healing of mucosal lesions. Based on the results of clinical studies, it has been established that taking 20 mg of rabeprazole 2 times / day in combination with two antibiotics, for example clarithromycin and amoxicillin or clarithromycin and metronidazole for 1 week, allows Helicobacter pylori eradication more than 80% in patients with gastroduodenal ulcers. When choosing the appropriate combination for the eradication of Helicobacter pylori should be guided by approved standards of treatment. In patients with persistent infection (in the presence of initially sensitive strains of microorganisms), it is necessary to consider the possibility of developing secondary resistance to antibacterial drugs when choosing a dosing regimen.
Effect on serum gastrin: in clinical trials, patients received rabeprazole 10 or 20 mg once per day for up to 43 months. The concentration of gastrin in the serum increased in the first 2-8 weeks of administration, reflecting the suppressive effect on the secretion of hydrochloric acid, and then remained stable while continuing therapy. The gastrin concentrations returned to baseline values ​​usually within 1-2 weeks after the withdrawal of therapy.
The biopsy specimens from the antral part and the bottom of the stomach obtained from more than 500 patients taking rabeprazole or comparative treatment for up to 8 weeks showed no changes in the ECL-cell and histological structure, the degree of gastritis, the incidence of atrophic gastritis, intestinal metaplasia or prevalence of H. pylori infection more than 250 patients, observed during 36 months of therapy, did not reveal significant changes in the original conditions.
Other effects: the systemic effect of rabeprazole on the central nervous system, cardiovascular and respiratory systems has not been identified to date. Rabeprazole, administered orally at a dose of 20 mg for 2 weeks, had no effect on thyroid function, carbohydrate metabolism or circulating concentrations of parathyroid hormone, cortisol, estrogens, testosterone, prolactin, cholecystokinin, secretin, glucagon, follicle stimulating hormone (FSH), luteinizing hormone (LH), renin, aldosterone or somatotropic hormone.
Clinical studies have shown that rabeprazole does not enter into a clinically significant interaction with amoxicillin, does not adversely affect the concentration of amoxicillin or clarithromycin in blood plasma, while using these drugs to eradicate Helicobacter pylori from the upper gastrointestinal tract.
PHARMACOKINETICS
Suction
The drug Zulbex В® is a tablets of rabeprazole, coated with an enteric (resistant in the stomach) shell. This form is due to the instability of rabeprazole in an acidic environment. Therefore, the absorption of rabeprazole begins only after the tablet has left the stomach. Suction fast; C max rabeprazole in blood plasma is achieved approximately 3.5 hours after ingestion at a dose of 20 mg. C max and AUC are linear in the dose range of 10 mg to 40 mg. Absolute bioavailability of the internal dose of 20 mg (compared with the intravenous administration) is approximately 52%, largely due to presystemic metabolism. With repeated use of bioavailability, apparently, does not increase. In healthy people, T 1/2 of blood plasma is approximately 1 hour (0.7 to 1.5 hours), and the total clearance is 283 В± 98 ml / min. There is no clinically significant interaction associated with ingestion. Neither the food nor the time of taking the drug does not affect the absorption of rabeprazole.
Distribution
In humans, rabeprazole binds approximately 97% to plasma proteins.
Metabolism and excretion
Rabeprazole, like other representatives of the proton pump inhibitor class, is metabolized in the liver, with the participation of cytochrome P450 (CYP450). In vitro studies with human hepatic microsomes showed that rabeprazole is metabolized by CYP450 isoenzymes (CYP2C19 and CYP3A4). In these studies, rabeprazole in the expected plasma concentrations in humans did not suppress or stimulate CYP3A4. These results indicate that no interaction is expected between rabeprazole and cyclosporin. In humans, the main metabolites found in the plasma are thioether (M 1 ) and carboxylic acid (M 6 ), and sulfonic (M 2 ), desmethyl thioether (M 4 ) and conjugate with mercapturic acid (M 5 ) are detected in smaller amounts . Only desmethyl metabolite (M 3 ) has low antisecretory activity, but it is not determined in plasma.
After a single oral administration of 20 mg of 14 C-labeled rabeprazole, unchanged rabeprazole is not excreted by the kidneys. Approximately 90% of the accepted dose is excreted by the kidneys in the form of two metabolites: conjugate with mercapturic acid (M 5 ) and carboxylic acid (M 6 ), and also in the form of two unknown metabolites. The rest of the injected drug is found in the contents of the intestine.
Pharmacokinetics in special clinical cases
Sex: adjusted for growth and body weight, no sex differences in the pharmacokinetic parameters of rabeprazole at a dose of 20 mg were found.
Impaired renal function: in patients with renal insufficiency requiring hemodialysis (CC less than 5 ml / min / 1.73 m 2 ), the distribution of rabeprazole was similar to its distribution in healthy volunteers. AUC and Cmax in such patients were approximately 35% lower than those in healthy volunteers. The mean T 1/2 of rabeprazole was 0.82 h in healthy volunteers, 0.95 h in patients with hemodialysis and 3.6 h after hemodialysis. CC of rabeprazole in patients with impaired renal function requiring maintenance hemodialysis was approximately 2 times higher than in healthy volunteers.
Impaired liver function: after a single application of rabeprazole in a dose of 20 mg in patients with mild or moderate liver disease, the AUC increased by 2 times, and T 1/2 of rabeprazole increased in comparison with healthy volunteers 2-3 times. However, after daily administration of 20 mg dose within 7 days, AUC increased only 1.5 times, and C max - only 1.2 times. T 1/2 of rabeprazole in patients with impaired liver function was 12.3 h compared to 2.1 h in healthy volunteers. The pharmacodynamic response (control of gastric pH) in the two groups was clinically comparable.
Elderly patients: in elderly patients the excretion of rabeprazole was slightly reduced. After using rabeprazole for 7 days at a daily dose of 20 mg, the AUC increased approximately 2-fold, and the C max increased by 60%, and T 1/2 was increased by 30% compared to healthy young volunteers. No evidence of rabeprazole accumulation was noted.
Polymorphism CYP2C19: after ingestion of rabeprazole at a dose of 20 mg in people with delayed CYP2C19 metabolism, AUC and T 1/2 were approximately 1.9 and 1.6 times higher than those in persons with active metabolism, while C max increased by only 40%.
INDICATIONS
- Stomach ulcer and duodenal ulcer in the phase of exacerbation;
- Gastroesophageal reflux disease (GERD): erosive reflux-esophagitis (treatment), symptomatic treatment of GERD, incl. long-term maintenance therapy;
- Zollinger-Ellison syndrome;
- as part of complex therapy: eradication of Helicobacter pylori in patients with peptic ulcer of stomach and duodenum or chronic gastritis;
- Treatment and prevention of recurrence of peptic ulcer associated with Helicobacter pylori.
DOSING MODE
Tablets are taken orally, whole, not liquid and not breaking.
With gastric ulcer and duodenal ulcer in the phase of exacerbation, the drug is prescribed 20 mg 1 once / day, in the morning. In most patients, active duodenal ulcer heals within 4 weeks. However, some patients may need another 4 weeks for complete healing of the ulcer. Active benign gastric ulcer in most patients heals within 6 weeks. However, in a small number of patients, it may take another 6 weeks for complete healing.
In gastroesophageal reflux disease (GERD): erosive reflux-esophagitis (treatment), symptomatic treatment of GERD drug is prescribed at 20 mg 1 time / day for 4 to 8 weeks. With prolonged therapy, a maintenance dose of Zulbex В® can be used - 10-20 mg 1 time / day, depending on the patient's response to treatment.
With symptomatic treatment of GERD - by 10 mg 1 time / day in patients without esophagitis. If the symptoms can not be controlled within 4 weeks, an additional examination of the patient is necessary. After improvement of the patient's condition, further control of the symptoms can be performed with 10 mg 1 time / day, on demand.
With Zollinger-Ellison syndrome, the recommended starting dose for adults is 60 mg 1 time / day. The dose can be increased to 120 mg / day, depending on the individual needs of the patient. You can appoint a daily dose to 100 mg 1 time / day. A dose of 120 mg may require a multiple admission, 60 mg 2 times / day. Therapy is performed as long as there are appropriate clinical indications.
Eradication of Helicobacter pylori in patients with peptic ulcer of stomach and duodenum or chronic gastritis: patients with Helicobacter pylori should undergo eradication therapy.
The following combinations of preparations are recommended for 7 days:
The drug Zulbex В® 20 mg 2 times / day + clarithromycin 500 mg 2 times / day and amoxicillin 1 g 2 times / day.
In patients with impaired renal and / or liver function correction of the dose of Zulbex В® is not required.
Due to insufficient data on efficiency and safety Rabeprazole Zulbecks В® is not used in children .
SIDE EFFECT
Classification of the incidence of adverse events WHO: very often (> 1/10), often (> 1/100 to <1/10), infrequently (> 1/1000 to <1/100), rarely (> 1 / 10 000 to <1/1000), very rarely (from <1/10 000, including individual messages).
In each group, adverse events are listed in order of decreasing severity.
From the hemopoietic system: rarely - neutropenia, leukopenia, thrombocytopenia, leukocytosis.
On the part of the immune system: rarely - the reaction of hypersensitivity (includes facial edema, decreased blood pressure, dyspnea).
Disorders of metabolism and nutrition: rarely - anorexia, weight gain; very rarely - hyponatremia.
From the nervous system: often - headache, dizziness, insomnia; infrequently - drowsiness, nervousness; rarely - depression; very rarely confusion.
From the senses: rarely - a vision disorder.
From the cardiovascular system: very rarely - peripheral edema.
From the respiratory system: often - cough, pharyngitis, rhinitis; infrequently - bronchitis, sinusitis.
On the part of the digestive system: often - diarrhea, vomiting, nausea, abdominal pain, constipation, flatulence; infrequently - dyspepsia, dryness of the oral mucosa, belching; rare gastritis, stomatitis, change in taste, hepatitis, jaundice, hepatic encephalopathy (rare reports of hepatic encephalopathy in patients with concomitant cirrhosis of the liver have been received.) When prescribing Zulbex В® for the first time, patients with severe impairment of liver function should be careful.
On the part of the skin: infrequent - rash, erythema; rarely - itching, sweating, bullous rash; very rarely erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome (erythema, bullous reactions and hypersensitivity reactions usually pass by themselves after the drug is withdrawn).
From the musculoskeletal system: often - nonspecific pain, back pain; infrequently - myalgia, spasms of calf muscles, arthralgia.
From the urinary system: infrequently - urinary tract infections; rarely interstitial nephritis.
From the side of the reproductive system: very rarely - gynecomastia.
Laboratory indicators: infrequently - increased activity of liver enzymes.
Other: often - asthenia, flu-like disease.
CONTRAINDICATIONS
- Pregnancy (there is no experience of application);
- the period of breastfeeding (no experience of use);
- Children's age (no experience of application);
- Hypersensitivity to the active substance or auxiliary components of the drug.
With caution should be used in severe renal failure.
PREGNANCY AND LACTATION
Pregnancy
There is no data on the safety of rabeprazole during pregnancy in humans. Reproductive studies in rats and rabbits showed no signs of impaired fertility or the harmful effects of rabeprazole on the fetus.
Zulbex В® is not used in pregnancy.
Lactation
It is not known whether rabeprazole is secreted into human milk, but secreted into the milk of rats. Studies in women during lactation were not conducted.
If you need Zulbex В® during lactation, breastfeeding should be discontinued.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution should be used in severe renal failure.
In patients with impaired renal function, dose adjustment of Zulbex В® is not required
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
In patients with impaired hepatic function correction of the dose of Zulbex В® is not required.
Against the background of the use of Zulbex В® it is possible to change the activity of liver enzymes that occur after the drug is discontinued.
In a study in patients with mild or moderate liver function abnormalities, there were no significant safety problems with the use of rabeprazole compared to the control group of healthy patients corresponding to sex and age. Due to the lack of clinical data on the use of rabeprazole in patients with severe impairment of liver function, caution is recommended when using Zulbex В® in this group of patients.
APPLICATION FOR CHILDREN
Due to the lack of data on the efficacy and safety of rabeprazole, Zulbecks is not used in children.
APPLICATION IN ELDERLY PATIENTS
In elderly patients, removal of rabeprazole was slightly reduced. After using rabeprazole for 7 days at a daily dose of 20 mg, the AUC increased approximately 2-fold, and the C max increased by 60%, and T 1/2 was increased by 30% compared to healthy young volunteers. No evidence of rabeprazole accumulation was noted.
SPECIAL INSTRUCTIONS
Reducing the severity of symptoms on the background of therapy with Zulbecks В® does not exclude the presence of malignant neoplasms in the stomach or esophagus, therefore, before the start of therapy it is necessary to conduct a survey in order to exclude the growth of the gastrointestinal tract.
Patients receiving long-term therapy with Zulbeks В® (especially more than one year) should undergo regular screening.
It is impossible to eliminate the risk of cross-reactions with other proton pump inhibitors or substituted benzoimidazole.
The patient should be warned that the pills must be poglatyvat whole without chewing or breaking a.
It has been reported post-marketing studies on the development of blood dyscrasias (thrombocytopenia and neutropenia cases) during treatment with rabeprazole. In most cases, when it is not possible to find out alternative causes of these conditions, they did not give complications and It took place after the abolition of rabeprazole.
Against the background of the drug Zulbeks В® possible change in the activity of liver enzymes, extending after drug withdrawal.
In a study in patients with mild to moderate hepatic impairment there were no major problems related to safety applications rabeprazole, compared with a control group of healthy patients, matched for sex and age. Due to lack of clinical data are rabeprazole in patients with severely impaired liver function, it is recommended to observe caution when applying Zulbeks preparation В® in this group of patients.
Use in Pediatrics
The drug Zulbeks В® is not recommended for children, because experience with the drug in this group of patients is not.
The effect on the ability to drive vehicles
Based on the properties of rabeprazole, it is unlikely that the drug Zulbeks В® may interfere with the ability to operate vehicles or affect the operation of the technical devices. In the case of side effects (drowsiness, dizziness, confusion) should abandon driving and work requiring high concentration and psychomotor speed reactions.
OVERDOSE
The existing experience of intentional or accidental overdose rabeprazole limited. The maximum amount of drug taken by the set does not exceed 60 mg of 2 times / day or 160 mg 1 time / day. Effects were mild, consistent with the known spectrum of adverse events, which were held on their own without any further medical intervention.
Treatment: symptomatic. The specific antidote is unknown. Dialysis is ineffective.
DRUG INTERACTION
Rabeprazole is stable and long lasting inhibition of gastric acid secretion in the stomach. May arise interaction with drugs, the absorption of which depends on the pH values.
Simultaneous application of rabeprazole with ketoconazole or itraconazole can lead to a significant reduction of their concentration in the blood plasma, and therefore may require adjustment of the dose of these drugs.
Proton pump inhibitors, including rabeprazole, should not be used concurrently with atazanavir.
Rabeprazole has no clinically significant interaction with amoxicillin and other drugs metabolized by cytochrome system enzymes CYP450, such as warfarin, phenytoin, theophylline and diazepam.
Rabeprazole slows elimination of certain drugs, metabolized in the liver by microsomal oxidation (diazepam, phenytoin, oral anticoagulants).
Rabeprazole and concentration of the active metabolite of clarithromycin in plasma while taking increased by 24% and 50%, respectively.
Rabeprazole while the application reduces the concentration of ketoconazole by 33%, 22% digoxin .
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 30 В° C. Shelf life - 2 years.
