Rabiet capsules enteric soluble 20mg, 14pcs

Composition

1 capsule contains:

Rabeprazole, substance-pellets 8.5% 236 mg

Active ingredient:  rabeprazole sodium 20 mg;

Auxiliary substances:  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;

Excipients for the shell of pellets:  Hypromellose phthalate 31.88 mg, cetyl alcohol 3.18 mg:

solid gelatin capsules No. 1:  capsule body and lid – titanium dioxide 2%, blue proprietary dye 0.0158%, gelatin up to 100%.

Pharmacological action

Pharmacotherapy group

Means that reduces the secretion of gastric glands-proton pump inhibitor.

ATX code: A 02 BC 04

Pharmacological properties

Pharmacodynamics

Mechanism of action

Rabeprazole sodium belongs to the class of antisecretory compounds derived from benzimidazole. Rabeprazole sodium suppresses gastric juice secretion by specifically inhibiting H+/K+ ATPases on the secretory surface of gastric parietal cells.

N+ / 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, regardless of the stimulus. Rabeprazole sodium has no anticholinergic properties.

Antisecretory action

After oral use 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 longer than the predictable half-life (half-life) (approximately 1 hour). This effect can be explained by prolonged binding of the drug substance to H+/K+ ATPase of gastric parietal cells.

The inhibitory effect of rabeprazole sodium on hydrochloric acid secretion reaches a plateau after three days of taking rabeprazole sodium. Upon discontinuation of the drug, secretory activity is restored within 1-2 days.

Effect on the level of gastrin in blood plasma

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

Effect on enterochromaffin-like cells

When examining human gastric biopsy samples from the antrum and gastric floor of 500 patients who received rabeprazole sodium or the reference drug for 8 weeks, no stable changes in the morphological structure of enterochromaffin-like cells, the severity of gastritis, the frequency of atrophic gastritis, intestinal metaplasia, or the spread of Helicobacter pylori infection were found.

In a study involving more than 400 patients treated with 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

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

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

Pharmacokinetics

Suction

Rabeprazole is rapidly absorbed from the intestine, and its maximum plasma concentrations are reached approximately 3.5 hours after taking a dose of 20 mg. Changes in the maximum plasma concentrations (with_max) of the site values under the concentration-time curve (AUC) of rabeprazole are linear in the dose range from 10 to 40 mg.

The absolute bioavailability after oral use of 20 mg (compared to intravenous use) is about 52%. In addition, the bioavailability does not change with repeated use of rabeprazole. In healthy volunteers, the plasma half-life 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 damage, the AUC was doubled compared to healthy volunteers, which indicates a decrease in first-pass metabolism, and the plasma half-life was increased by 2-3 times. Neither the time of taking the drug during the day, nor antacids do not affect the absorption of rabeprazole.

Taking the drug with fatty foods reduces the absorption of the drug for 4 hours or more, but neither with_max, nor the degree of absorption does not change.

Distribution

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

Metabolism.

In healthy people. After taking a single oral dose of 20 mg of 14C-labeled rabeprazole, no unchanged drug was found in the urine.

About 90% of rabeprazole is excreted through the kidneys, mainly in the form of two metabolites: a conjugate of mercapturic acid (M5) and carboxylic acid (M6), as well as in the form of two unknown metabolites detected during toxicological analysis. The remainder of rabeprazole sodium taken is excreted through the intestines.

The total elimination rate is 99.8%. These data indicate a small excretion of rabeprazole sodium metabolites in the bile.

The main metabolite is thioester (M1). The only active metabolite is desmethyl (M3), but it was observed in low concentrations in only one study participant after taking 80 mg of rabeprazole sodium.

End-stage renal failure

In patients with stable end-stage renal insufficiency who require maintenance hemodialysis (Creatinine clearance AUC and_cmax in these patients were approximately 35% lower than in healthy volunteers.

On average, the half-life of rabeprazole is 0.82 hours in healthy volunteers; 0.95 hours in patients during hemodialysis and 3.6 hours 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 of the liver tolerate rabeprazole sodium at a dose of 20 mg once a day, although the AUC is doubled and the_cmax is increased by 50% compared to healthy volunteers of the corresponding sex.

Elderly patients

In elderly patients, the elimination of rabeprazole is somewhat delayed. After 7 days of taking rabeprazole 20 mg, the AUC was approximately twice as high in the elderly, and the_cmax was increased by 60% compared to young healthy volunteers. However, there were no signs of accumulation of rabeprazole.

CYP2C19 polymorphism.

In patients with slow CYP2C19 metabolism, after 7 days of taking rabeprazole at a dose of 20 mg per day, the AUC increases by 1.9 times, and the half-life increases by 1.6 times compared to the same parameters for “fast metabolizers”, while the_cmax increases by 40%.

Indications

Symptoms of dyspepsia associated with increased acidity of gastric juice, including symptoms of gastroesophageal reflux disease (heartburn, acid belching).

Use during pregnancy and lactation

There are no data on the safety of rabeprazole use during pregnancy. Reproductive studies in rats and rabbits have not shown signs of fertility disorders or fetal defects caused by rabeprazole; however, in rats, the drug penetrates the placental barrier in small amounts.

Rabiet®preparation it should not be used during pregnancy unless the expected positive effect for the mother outweighs the possible risk to the fetus.

It is not known whether rabeprazole is excreted in breast milk. No relevant studies have been conducted in breastfed women. However, rabeprazole is found in the milk of lactating rats, so Rabiet®should not be prescribed to women during breastfeeding.

Contraindications

• Sucrose/isomaltase deficiency, fructose intolerance, glucose-galactose malabsorption syndrome;

• pregnancy;

• breast-feeding period;

• age up to 18 years;

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

With caution, the drug should be prescribed for severe renal failure.

Side effects

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 transient.

When using rabeprazole in clinical trials, the following side effects were noted.

Nervous system disorders: headache, dizziness.

From the digestive system: abdominal pain, diarrhea, flatulence, constipation, dry mouth.

Other services: rash, peripheral edema.

The following side effects were reported during post-marketing use of the drug.

From the digestive system: increased activity of liver enzymes; rarely-hepatitis, jaundice. Hepatic encephalopathy has rarely been reported in patients with cirrhosis of the liver.

From the hematopoietic system: rarely-thrombocytopenia, neutropenia, leukopenia.

Musculoskeletal disorders: rarely-myalgia, arthralgia.

Allergic reactions: rarely-bullous rashes, urticaria, acute systemic allergic reactions; very rarely-erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Other services: rarely-hypomagnesemia; very rarely – development of interstitial nephritis, gynecomastia.

No changes in other laboratory parameters were observed during rabeprazole sodium use.

According to post-marketing surveillance data, taking proton pump inhibitors may increase the risk of fractures.

Interaction

The cytochrome 450 system

Rabeprazole sodium, like other proton pump inhibitors, is metabolized by the cytochrome p450 (CYP450) system in the liver. In vitro studies on human liver microsomes have shown that rabeprazole sodium is metabolized by CYP2C19 and CYP3A4 isoenzymes.

Studies in healthy volunteers have shown that rabeprazole sodium has no pharmacokinetic or clinically significant interactions with drugs that are metabolized by the cytochrome p450 system-warfarin, phenytoin, theophylline and diazepam (regardless of how diazepam is metabolized in patients, heavily or weakly).

A study of combination therapy with antibacterial drugs was conducted. This four-way study included 16 healthy volunteers who received 20 mg of rabeprazole,1000 mg of amoxicillin,500 mg of clarithromycin, or a combination of these three drugs (CANCER – rabeprazole, amoxicillin, clarithromycin).

The AUC and Cmax values for clarithromycin and amoxicillin were similar when compared with combination therapy and monotherapy. The AUC and Cmax values for rabeprazole increased by 11% and 34%, respectively, and for 14-hydroxyclarithromycin (the active metabolite of clarithromycin), the AUC and Cmax values increased by 42% and 46%, respectively, for combination therapy compared to monotherapy.

This increase in rabeprazole and clarithromycin exposure was not considered clinically significant.

Interactions due to inhibition of gastric juice secretion

Rabeprazole sodium provides stable and prolonged suppression of gastric juice secretion. Thus, interaction with substances for which absorption depends on pH can occur. When taken concomitantly with rabeprazole sodium, ketoconazole absorption decreases by 30%, and digoxin absorption increases by 22%.

Therefore, some patients should be monitored to determine whether dose adjustment is necessary when rabeprazole sodium is co-administered with ketoconazole, digoxin, or other medications for which absorption depends on pH.

Atazanavir

Concomitant use of atazanavir 300 mg/ritonavir 100 mg with omeprazole (40 mg 1 time / day) or atazanavir 400 mg with lansoprazole (60 mg 1 time / day) in healthy volunteers, a significant reduction in exposure to atazanavir was observed. Absorption of atazanavir depends on pH.

Although concomitant use with rabeprazole has not been studied, similar results are also expected for proton pump inhibitors. Therefore, concomitant use of atazanavir with proton pump inhibitors, including rabeprazole, is not recommended.

Antacids

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

Food intake

In a clinical study, no clinically significant interaction was observed during the use of rabeprazole sodium with a fat-depleted diet. Taking rabeprazole sodium concomitantly with a fat-rich diet may slow the absorption of rabeprazole for up to 4 hours or more, but Cmax and AUC do not change.

Cyclosporine

In vitro experiments using human liver microsomes have shown that rabeprazole inhibits cyclosporine metabolism with an IC50 of 62 micromol, i. e. at a concentration 50 times higher than the Cmax for healthy volunteers after 20 days of taking rabeprazole at a dose of 20 mg. The degree of inhibition is similar to that of omeprazole at equivalent concentrations.

Methotrexate

According to reports of adverse events, published pharmacokinetic studies, and retrospective analysis, it can be assumed that concomitant use of proton pump inhibitors and methotrexate (especially at high doses) may lead to an increase in the concentration of methotrexate and/or its metabolite hydroxymethotrexate and prolong its elimination time.

However, no specific studies have been conducted on the drug interaction of methotrexate with proton pump inhibitors.

How to take, course of use and dosage

The drug is taken orally, preferably in the morning, before meals. It was found that neither the time of day nor food intake affects the activity of rabeprazole sodium, but the recommended time of taking rabeprazole contributes to better compliance of patients with the treatment regimen. Capsules should be swallowed whole, without chewing or crushing.

The recommended dose is 10 mg 1 time/day.

If there is no effect during the first 3 days of treatment, a specialist examination is necessary.

The maximum course of treatment without consulting a doctor is 14 days.

Overdose

Data on intentional or accidental overdose are minimal.

There were no cases of severe overdose of rabeprazole.

Treatment: conducting symptomatic and supportive care.

The specific antidote for rabeprazole is unknown.

Rabeprazole binds well to plasma proteins, so it is poorly excreted during dialysis.

Special instructions

The patient’s response to rabeprazole sodium therapy does not exclude the presence of malignancies in the stomach.

In a special study in patients with mild or moderate hepatic impairment, there was no significant difference in the frequency of side effects of rabeprazole from those in healthy individuals selected by gender and age, but despite this, caution is recommended when using Rabiet® for the first time in patients with severe hepatic impairment.

In patients with impaired renal or hepatic function, adjust the dose of Rabiet® not required. The AUC of rabeprazole sodium in patients with severe hepatic impairment is approximately 2 times higher than in healthy patients.

Hypomagnesemia

When treated with proton pump inhibitors for at least 3 months, cases of symptomatic or asymptomatic hypomagnesemia have been reported in rare cases. In most cases, these reports were received one year after the therapy. Serious side effects were tetany, arrhythmia, seizures.

Most patients required treatment for hypomagnesaemia, including magnesium replacement and withdrawal of proton pump inhibitors. In patients who will be receiving long-term treatment or who are taking proton pump inhibitors with drugs such as digoxin or drugs that may cause hypomagnesemia (for example, diuretics), magnesium concentrations should be monitored before starting treatment with proton pump inhibitors and during treatment.

Do not take other acid-reducing agents, such as H2-histamine receptor blockers or proton pump inhibitors, at the same time as Rabiet®.

Bone fractures

Observational studies suggest that proton pump inhibitor therapy may increase the risk of osteoporosis-related hip, wrist, or spinal fractures. The risk of fractures was increased in patients who received high-dose proton pump inhibitors for a long time (one year or more). High doses should be understood as those that exceed those recommended in the instructions.

Concomitant use with methotrexate

According to literature data, concomitant use of proton pump inhibitors with methotrexate (primarily in high doses) can lead to an increase in the concentration of methotrexate and/or its metabolite hydroxymethotrexate and prolong the time of its elimination, which can lead to the manifestation of methotrexate toxicity. If it is necessary to use methotrexate in high doses, the possibility of temporarily stopping therapy with proton pump inhibitors may be considered.

Clostridium difficile

Proton pump inhibitor therapy may increase the risk of gastrointestinal infections, such as those caused by Clostridium difficile.

Patients taking rabeprazole for short-term symptomatic treatment of symptoms of GERD and NERD (such as heartburn) without a prescription should consult a doctor in the following cases::

– the use of remedies to relieve symptoms of heartburn and digestive disorders for 4 weeks or more;

– the appearance of new symptoms or changes in previously observed symptoms in patients over the age of 55 years;

– cases of unintentional weight loss, anemia, gastrointestinal bleeding, dysphagia, pain when swallowing, constant vomiting or vomiting with blood and stomach contents, cases of stomach ulcers or gastric surgery in the anamnesis, jaundice, etc. (including