"Rabeprazole": instructions for use, what helps, where to buy

With gastritis, ulcers and other lesions of the stomach, increased secretion of hydrochloric acid is observed - the main component of gastric juice. The result is ulcers, pain, digestive disorders and other consequences. Various medications are used to prevent it, including Rabeprazole. This is an effective remedy at an affordable price.

"Rabeprazole" composition and description

The drug is available in the form of capsules, which dissolve when entering the intestines. The active ingredient is rabeprazole sodium (10 or 20 mg in each capsule). The drug has an antiulcer effect.

It affects enzymes that are synthesized by the parietal cells of the stomach. As a result, hydrochloric acid is partially blocked, which reduces the secretion of gastric juice even with food intake. The active substance is completely absorbed within 3-4 hours. Moreover, the bioavailability of the drug does not depend on what time the capsules are taken.

The product should be stored under normal room conditions, away from direct sunlight. Access for children is excluded. The general shelf life is 2 years from the date of production.

Rabeprazole

Rabeprazole

(lat.
rabeprazole
) - antiulcer medicine, proton pump inhibitor. Rabeprazole is the international nonproprietary name (INN) of the drug. According to the pharmacological index, rabeprazole belongs to the group “Proton pump inhibitors”. According to ATC, it belongs to the group “Proton pump inhibitors” and has the code A02BC04. Rabeprazole, in addition, the trade name of the drug is a Russian-made generic.

Rabeprazole is a chemical substance

Rabeprazole is a substituted benzimidazole derivative: 2-[[[4-(3-Methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]benzimidazole. The empirical formula is C18H21N3O3S. Molecular weight 381.43. Rabeprazole sodium is a white or slightly yellowish-white substance, very soluble in water and methanol, soluble in ethanol, chloroform and ethyl acetate and insoluble in ether and n-hexane. Weak foundation. The stability of rabeprazole depends on the acidity of the environment - it is quickly destroyed in moderate acids and is more stable in an alkaline environment.

Indications for use of rabeprazole

• gastric ulcer (GUD) and duodenal ulcer (DU) in the acute stage
• gastroesophageal reflux disease (GERD)
• pathological hypersecretion of hydrochloric acid, including Zollinger-Ellison syndrome
• eradication of Helicobacter pylori in patients with gastritis or chronic gastritis (only as part of combination therapy with antibiotics)
• treatment and prevention of relapses of peptic ulcer associated with Helicobacter pylori (only as part of combination therapy with antibiotics)

Contraindications to the use of rabeprazole

• hypersensitivity to rabeprazole
• pregnancy
• lactation

Restrictions on the use of rabeprazole

• severe liver failure
• childhood
• Long-term or high-dose use of rabeprazole increases the risk of hip, wrist, and spine fractures (“FDA Warns”)

Method of administration of rabeprazole and dose

Rabeprazole tablets are swallowed whole without chewing or crushing. Doses and duration of use of rabeprazole depend on the disease:

• Peptic ulcer in the acute stage - 20 mg once a day for 4 weeks, with poor healing - additionally for another 4 weeks
• DU - 10 or 20 mg once a day for 6 weeks, if healing is poor - another 6 weeks
• GERD - 20 mg once a day for 4-8 weeks, maintenance therapy is possible in the future: 10-20 mg once a day
• eradication of Helicobacter pylori as part of triple therapy: rabeprazole 20 mg twice a day, clarithromycin - 500 mg per day and amoxicillin - 1000 mg per day for 7 days (see also Standards for the diagnosis and treatment of acid-related and Helicobacter pylori-associated diseases, which also present other eradication schemes).

Time of administration and food do not affect the activity of rabeprazole, but it is believed that patients comply better with the prescribed treatment regimen if rabeprazole is taken in the morning, half an hour before meals (with a single dose per day).
There are studies proving that dividing the daily dose of rabeprazole into 2-4 doses per day reduces stomach acidity, however, such split doses may have a downside - a decrease in adherence to treatment (Evsyutina Yu.V.).

Over-the-counter rabeprazole medications

In Russia, in particular, the following rabeprazole preparations are approved for over-the-counter sale: Bereta, Noflux, Pariet, Rabiet, capsule dosage form containing 10 mg of rabeprazole sodium (or rabeprazole).
The general rule when taking over-the-counter proton pump inhibitors (including rabeprazole): if there is no effect within the first three days, consultation with a specialist is necessary. The maximum period of treatment with over-the-counter proton pump inhibitors without consulting a doctor is 14 days. The interval between 14-day courses must be at least 4 months. Rabeprazole in a reduced dose compared to the therapeutic dose has been approved for sale in pharmacies in Australia since 2010, and later in the UK.*

All over-the-counter forms have a reduced content of active substance and are intended “for the treatment of frequent heartburn.”

* Boardman HF, Heeley G. The role of the pharmacist in the selection and use of over-the-counter proton-pump inhibitors. Int J Clin Pharm (2015) 37:709–716. DOI 10.1007/s11096-015-0150-z.

Publications for Health Professionals

• Pakhomova I.G. A multimorbid patient with GERD and pathology of the cardiovascular system receiving antiplatelet therapy. Possibility of choosing a proton pump inhibitor using a clinical example. Medical advice. 2019;(14):10-16.
• Maev I.V., Goncharenko A.Yu., Kucheryavyi Yu.A. The effectiveness of monotherapy with omeprazole and rabeprazole in patients with erosive reflux esophagitis in old age // Clinical perspectives of gastroenterology and hepatology. – 2007. – No. 2. – p. 31–36.
• Warrington Steve, Baisley Kathy, Dunn Kate et al. Effects of a single dose of rabeprazole 20 mg and esomeprazole 40 mg on intragastric 24-hour pH measurements in healthy volunteers // Eur J Clin Pharmacol. – 2006. – No. 62. - With. 685–691.
• Khavkin A.I., Rachkova N.S., Zhikhareva N.S., Khanakaeva Z.K. Prospects for the use of proton pump inhibitors in pediatrics // Russian Medical Journal. – 2003. – Volume 11. – No. 3. – p. 134–138.
• Morozov S.V., Tsodikova O.M., Isakov V.A. and others. Comparative effectiveness of the antisecretory action of rabeprazole and esomeprazole in individuals who rapidly metabolize proton pump inhibitors // Experimental and clinical gastroenterology. – 2003. – No. 6.
• Rudakova A.V. Pharmacoeconomic aspects of the use of rabeprazole and esomeprazole in patients with gastroesophageal reflux disease // Consilium-Medicum. – 2006. – Volume 8. – No. 2.
• Yastrebkova L.A. Comparative clinical effectiveness and safety of rabeprazole (Pariet) and esomeprazole (Nexium) in the treatment of acid-related diseases of the gastrointestinal tract // MEDGAZETA. 07/08/2009.
• Abdulganieva D.I. Variability of daily pH-metry in patients with duodenal ulcer after a single dose of rabeprazole // RZHGGK 2010. No. 6. P. 76–80.
• Marelli S., Pace F. Use of rabeprazole for the treatment of acid-related diseases // Reprint. Expert Review Gastroenterology & Hepatology 6 (4), 423-435 (2012).
• Shulpekova Yu.O. The use of rabeprazole in the practice of a gastroenterologist // Medical Council. Gastroenterology. No. 14. 2016, pp. 26-31.
• Kareva E.N. Rabeprazole through the prism of “metabolism - effectiveness” // RMJ. 2021. October.
• Starodubtsev A.K., Fedorov S.P., Serebrova S.Yu. and others. Evaluation of the clinical effectiveness of rabeprazole depending on the individual type of parietal cell reception in various acid-dependent diseases. stomach and duodenum // Biomedicine. 2010. No. 1. P. 69–77.
• Bakulin I.G., Tikhonov S.V., Bakulina N.V., Zhuravleva M.S., Bordin D.S., Vasiliev R.V. Ineffectiveness of GERD therapy: risk factors and treatment reserves. Opinion Leader. No. 38. 2021. Interdisciplinary approach: rheumatology, gastroenterology. P.31-38..

On the website GastroScan.ru in the “Literature” section there is a subsection “Rabeprazole”, containing publications for healthcare professionals on the treatment of the gastrointestinal tract with rabeprazole.

Videos (reports and lectures) for healthcare professionals

On the website GastroScan.ru in the “Video” section there is a subsection “For Doctors”, containing video recordings of reports, lectures, webinars in various areas of gastroenterology for healthcare professionals.

Pharmacokinetics of rabeprazole

Rabeprazole is rapidly absorbed from the small intestine, with Cmax in blood plasma reached approximately 3.5 hours after taking a dose of 20 mg.
Cmax and AUC are linearly dependent on the dose of rabeprazole over the dose range from 10 to 40 mg. Bioavailability after oral administration of 20 mg is approximately 52%, mainly due to first-pass metabolism through the liver. Bioavailability does not change with repeated doses of rabeprazole. In healthy people, T½ of rabeprazole from blood plasma is about an hour (40–90 min), and the total clearance is (283 ± 98) ml/min. In patients with chronic liver diseases, AUC is two times higher than in healthy people, indicating a decrease in first-pass metabolism, and T½ of rabeprazole from blood plasma is increased by 2-3 times. Food and time of administration during the day do not affect the absorption of rabeprazole.

The degree of binding of rabeprazole to plasma proteins is about 97%.

The main metabolites present in blood plasma are thioester and carboxylic acid. In addition, minor metabolites are present in small concentrations: sulfone, demethylthioether and mercapturic acid conjugate.

After a single dose of 20 mg of rabeprazole, labeled with the 14C carbon isotope, no excretion of rabeprazole unchanged in the urine is observed. About 90% of rabeprazole is excreted in the urine in the form of two metabolites: a conjugate of mercapturic acid and carboxylic acid, and about 10% in feces.

After a single dose of 20 mg of rabeprazole with similar body weight and height, there are no noticeable differences in pharmacokinetics in men and women.

In patients with stable end-stage renal failure requiring hemodialysis (creatinine clearance ≤5 ml/min/1.73 m2), the distribution of rabeprazole differs little from the distribution in healthy people. AUC and Cmax in such patients are approximately 35% lower than in healthy controls. On average, T½ of rabeprazole was 0.82 hours in healthy people, 0.95 hours in patients undergoing hemodialysis, and 3.6 hours after hemodialysis. The clearance of rabeprazole in patients with kidney disease requiring hemodialysis is approximately 2 times higher than in healthy people.

After a single dose of 20 mg of rabeprazole in patients with chronic liver failure, the AUC doubles and T½ increases 2-3 times compared to healthy people. After taking rabeprazole 20 mg per day for 7 days, AUC increases only 1.5 times, and Cmax increases by 1.2 times. T½ of rabeprazole in patients with liver failure is approximately 12.3 hours compared to 2.1 hours in healthy people. The pharmacodynamic response observed using intragastric pH-metry was similar in both groups.

In elderly patients, the elimination of rabeprazole is slowed down. After 7 days of rabeprazole 20 mg per day, the AUC was approximately twice as high and the Cmax was increased by 60% in elderly patients compared to young and healthy patients. However, there are no signs of accumulation of rabeprazole.

In patients with slow metabolism of CYP2C19, after 7 days of taking rabeprazole at a dose of 20 mg per day, AUC increases by 1.9 times and T½ by 1.6 times compared to the same parameters in patients with rapid metabolism, while Cmax increases by 40%.

Pharmacodynamics of rabeprazole

In the acidic environment of the parietal cells of the gastric mucosa, rabeprazole is converted into the active sulfenamide form, which interacts with the proton pump (H+/K+-ATPase).
Inhibits (partially reversibly) the proton pump of parietal cells and dose-dependently blocks the secretion of hydrochloric acid. The antisecretory effect of rabeprazole appears within an hour after oral administration of a dose of 20 mg. The maximum decrease in stomach acidity occurs 2-4 hours after taking the first dose. On the first day, it reduces the average daily acidity level by 6% (this is about 88% of the reduction in secretion achieved on the 8th day of treatment). The acidity of the stomach on average per day is approximately 3.4 pH; the time during which acidity remains above 3 pH - 55.8%. Partial dissociation of the complex with the proton pump causes a shorter duration of action than that of irreversible proton pump inhibitors. The duration of inhibition of basal and stimulated secretion reaches two days, a stable antisecretory effect develops after three days of treatment. Withdrawal is not accompanied by the phenomenon of acid rebound; restoration of secretory activity occurs within 2–3 days as new proton pumps are synthesized. It has anti-Helicobacter activity: the minimum inhibitory concentration is 4–16 μg/ml. Accelerates the manifestation of anti-Helicobacter activity of a number of antibiotics. When carrying out triple eradication therapy (rabeprazole 20 mg twice daily with clarithromycin and amoxicillin) 90% eradication of Helicobacter pylori

(Нр) is achieved within 4 days. Hp eradication at the end of a 7-day course of therapy is observed in 100, 95, 90 and 63% of cases, respectively, when treated with rabeprazole in combination with clarithromycin + metronidazole, clarithromycin + amoxicillin, amoxicillin + metronidazole, or clarithromycin alone. For erosive or ulcerative gastroesophageal reflux disease, it reduces heartburn from the first day of treatment (10–20 mg). Effective in 8-week treatment of erosive reflux esophagitis in 84% of patients. Also effective in pathological hypersecretory conditions, including Zollinger-Ellison syndrome. In the first 2–8 weeks of long-term use, the concentration of gastrin in the blood serum temporarily increases (histological examination does not show an increase in the number of enterochromaffin-like cells, the frequency of intestinal metaplasia, or Hp colonization). When taking acid-resistant enteric-coated tablets orally, absorption begins in the small intestine and is rapid and complete. Absolute bioavailability - 52% (pronounced “first pass” effect through the liver). Food and timing of rabeprazole do not alter bioavailability. Cmax is achieved within 2–5 hours (on average 3.5 hours) after taking a dose of 20 mg. There is a linear dependence of the Cmax and AUC values ​​on the dose in the range from 10 to 40 mg. T½ is 0.7–1.5 hours; total clearance - 283 ml/min. Against the background of hepatic cell failure, the “first pass” effect through the liver is not expressed, AUC is increased by 2 times (after a single dose) and 1.5 times (after 7 days of therapy), T½ reaches 12.3 hours. Rabeprazole is metabolized in the liver with the participation of cytochrome P450 isoenzymes CYP2C19 and CYP3A4 with the formation of inactive metabolites and demethylthioether, which has weak antisecretory activity. In the case of delayed biotransformation, after 7 days of administration at a dose of 20 mg/day, T½ reaches 1–2 hours (on average 1.6 hours), Cmax increases by 40%. It is excreted primarily in the urine in the form of conjugates of mercapturic and carboxylic acids. In old age, the biotransformation of rabeprazole slows down, Cmax increases by 60%, AUC - 2 times. Even at the stage of end-stage renal failure in patients on dialysis, the pharmacokinetic parameters change slightly - Cmax and AUC decrease by 35%, T½ during hemodialysis is 0.95 hours, after - 3.6 hours.

Use of rabeprazole during pregnancy and breastfeeding

The FDA fetal risk category for rabeprazole in pregnant women is C* (animal studies have shown adverse effects on the fetus and there have been no adequate studies in pregnant women, but the potential benefits associated with the use of this drug in pregnant women may justify its use, despite the risk).
Breastfeeding should be stopped during treatment.

Note. *Previously, until 2014, rabeprazole was category B.

Side effects of rabeprazole

• digestive system: diarrhea, nausea; less often - vomiting, abdominal pain, flatulence, constipation; rarely - dry mouth, belching, dyspepsia; in isolated cases - impaired taste, anorexia, stomatitis, gastritis, increased transaminase activity
• nervous system and sensory organs: headache; less often - dizziness, asthenia, insomnia; very rarely - nervousness, drowsiness; in some cases - depression, visual impairment
• musculoskeletal system: rarely - myalgia; very rarely - arthralgia, calf muscle cramps
• respiratory organs: rarely - inflammation or infection of the upper respiratory tract, severe cough; very rarely - sinusitis, bronchitis
• allergic manifestations: rarely - rash, skin itching
• other: rarely - pain in the back, chest, limbs, swelling, urinary tract infection, fever, chills, flu-like syndrome; in isolated cases - increased sweating, weight gain, leukocytosis

Interaction of rabeprazole with other drugs

Rabeprazole reduces the concentration of ketoconazole in plasma by 33%, increases the concentration of digoxin by 22%.
Does not interact with liquid antacids. Rabeprazole is compatible with drugs metabolized by the P450 system, such as warfarin, phenytoin, theophylline and diazepam. If it is necessary to take proton pump inhibitors and clopidogrel simultaneously, the American Heart Association recommends taking pantoprazole instead of rabeprazole (Bordin D.S.). However, recently there have been publications claiming that rabeprazole should be the drug of choice among other PPIs when taking clopidogrel and PPIs together (Pakhomova I.G.).

Rabeprazole overdose

There are no known symptoms of rabeprazole overdose. If an overdose of rabeprazole is suspected, supportive and symptomatic therapy is recommended. Dialysis is ineffective.

Precautions during rabeprazole therapy

Before starting treatment with rabeprazole, it is necessary to exclude a malignant neoplasm of the stomach, since symptomatic improvement when taking rabeprazole may complicate timely diagnosis. Caution is recommended when first prescribing rabeprazole to patients with severely impaired liver function. If drowsiness occurs, you should avoid driving and other similar activities. Patients receiving ketoconazole or digoxin concomitantly with rabeprazole require additional monitoring, as dosage adjustments of these drugs may be required.

Comparison of rabeprazole with other proton pump inhibitors

On the Russian market, rabeprazole is sold in its original form under the brand name “Pariet”. Being one of the most modern drugs that reduce gastric acidity, Pariet differs from other antisecretory drugs in its high price. Russian gastroenterologists do not have a consensus regarding the unique properties and cost-effectiveness of using Pariet. These issues are discussed in more detail in the article “ Pariet
” in the section “Comparison of Pariet with other proton pump inhibitors.”

Slide from the report by S.Yu. Serebrova “Original PPIs and generics: modern problems of assessing substitution” at the Eschevod-2015 conference

In the work of Yu.M. Spivakovsky et al. it is stated that omeprazole and rabeprazole showed comparable effectiveness, safety profile, and tolerability when used in the course of treatment of chronic hepatitis in children and that no significant advantages were noted for each of the drugs.

Medicines containing the active ingredient rabeprazole

In Russia, the following drugs with the active ingredient rabeprazole are registered for sale in pharmacies: Bereta (Veropharm, Russia), Zulbex, Noflux (former name Zolispan), Ontime, Pariet (manufactured by Eisai Co.Ltd (Japan), Janssen Pharmaceutica (Italy), Jansen (Belgium)), Rabeloc, Rabeprazole-OBL (produced by the Russian company Obolenskoye), Rabeprazole-SZ, Rabiet, Razo, Khairabezol.
Most of them are available in the form of tablets for oral administration, coated with an intestinal soluble coating, containing 10 or 20 mg of the active substance - rabeprazole. In the USA and several other countries, Pariet is sold under the brand name AcipHex.

In a number of countries - former republics of the USSR, medicines with the active substance rabeprazole produced by Macleods Pharmaceuticals Ltd, India, are registered, in particular: in Kazakhstan

- Rabemak 10 and Rabemak 20,
in Ukraine
- Rabimak (Ukrainian rabіmak), as well as Rabelok (Ukrainian Rabelok) produced by Cadila Pharmaceuticals, Ltd., India In addition, there are a number of others on the pharmaceutical markets of the former USSR republics in Russia, drugs with the active substance rabeprazole, in particular: Barol-20 (Themis Laboratories Pvt. Ltd., India), Geerdin - powder for the preparation of solution for injection and enteric-coated tablets (Mepro Pharmaceuticals, India and Mili Healthcare Ltd , UK), Rabezol (Med-Interplast, India), Rabeprazole-health (Ukraine), Razol-20 (Biogenics Limited, India) and others.

In addition, specifically for the eradication of Helicobacter pylori

Combination medications are produced that contain drugs that correspond to one of the eradication regimens. An example of such a medicine presented on the Ukrainian market is ornistat, containing rabeprazole and two antibiotics: clarithromycin and ornisadol.

The optical isomer of rabeprazole, dexrabeprazole, has been included in the ATC since 2015 and is assigned the code A02BC07.

Doctor of Medical Sciences
D.S. Bordin presents the results of daily pH monitoring of a patient before and after parenteral administration of rabeprazole (40th Scientific Session of the Central Research Institute of Gastroenterology). Rabeprazole has contraindications, side effects and application features; consultation with a specialist is necessary. Back to section

Indications for use

The drug has antiulcer activity. It is prescribed in the presence of such pathologies:

• stomach ulcer;
• ulcerative lesions of the duodenum (also during an exacerbation);
• increased secretion of gastric shock;
• Zollinger-Ellison syndrome;
• gastritis of various types, including chronic (in this case, antibacterial drugs are taken simultaneously);
• relapses of peptic ulcer associated with the action of the bacterium Helicobacter pylori;
• reflux disease of the gastroesophageal type.

Contraindications and side effects

In some cases, taking the drug is excluded:

• hypersensitivity to the active ingredient;
• pregnancy period;
• breastfeeding period.

When taking the drug, side effects may occur from both the digestive system and other systems:

• loss of appetite;
• flatulence;
• constipation;
• nausea, vomiting;
• diarrhea;
• headaches;
• dizziness;
• drowsiness;
• taste disturbances;
• stomatitis;
• visual impairment;
• myalgia;
• pain in the spine;
• feverish condition;
• convulsions;
• arthralgia;
• allergic reactions (rash);
• cough;
• sinusitis;
• runny nose.

If the described phenomena occur, the drug should be stopped. Consultation with a doctor and symptomatic treatment are indicated.

Instructions for use "Rabeprazole"

The drug is taken orally with water. The initial dosage is from 10 to 20 mg of the active substance, which corresponds to 1-2 capsules. The total amount and duration of the course depend on the nature of the disease. The appointment is carried out on the recommendation of a doctor. No cases of overdose have been reported to date.

Important!

In childhood, taking the drug is not recommended, since relevant studies on the effect of the drug on health have not been conducted.

Biowaiver: rabeprazole and its generic analogues

The appearance of a large number of generic drugs on the domestic pharmaceutical market confronts the practicing physician with a difficult choice of which one to give preference to. The study of the interchangeability of drugs can greatly influence the improvement of the effectiveness and safety of pharmacotherapy. The article discusses the results of in vitro tests using the “biowaiver” procedure for the reference drug rabeprazole and its generic analogues. The results of the comparative dissolution kinetics test showed that only two of the six drugs studied correspond to the reference rabeprazole.

Rice. 1. Dissolution profiles of rabeprazole from tablets (R, R1, R2, R5, R6) and capsules (R3, R4) in PBS pH 6.8

Rice. 2. Dissolution profiles of rabeprazole from tablets (R, R1, R2, R5, R6) and capsules (R3, R4) in a pH 4.5 environment

Rice. 3. Dissolution profiles of rabeprazole from tablets (R, R1, R2, R5, R6) and capsules (R3, R4) in an environment with pH 1.2

Similarity coefficients (f2) of dissolution profiles of rabeprazole from 20 mg tablets and capsules in various media

Rice. 4. The ratio of sales volumes of original and generic drugs on the Russian pharmacy market for the first nine months of 2021 and 2021.

Introduction

An important trend in the development of the modern pharmaceutical market is the high degree of saturation of its basic segments due to the introduction of generic medicinal products (MDs) [1]. This direction of development is mainly associated with an increase in demand for non-original drugs, which is explained primarily by the economic component. A simplified procedure for state registration of generic drugs and their lower cost make it possible to reduce costs for manufacturers and consumers [2].

Currently, there is no generally accepted definition interpreting the term “generic”. According to the definition of the World Health Organization (WHO), this is a medicinal product that has proven therapeutic interchangeability with the original drug of a similar composition, produced by a manufacturer other than the original developer without a developer’s license. Experts from the European Medicines Agency (EMA) define a generic as a drug with the same qualitative and quantitative composition of the active substance and in the same pharmaceutical form as the original drug, demonstrating bioequivalence to the reference (standard) drug when conducting bioavailability tests [ 3].

In the Russian Federation, in accordance with the Federal Law of April 12, 2010 No. 61-FZ (as amended on December 27, 2021) “On the Circulation of Medicines,” the concepts of reproduced and reference medicines are established.

Reference drug is a drug that was first registered in Russia, the quality, effectiveness and safety of which have been proven based on the results of preclinical studies of drugs and clinical studies of drugs conducted in accordance with the requirements of parts 6 and 7 of Article 18 of the above law in relation to drugs for medical use.

A generic drug is a drug that has the same qualitative and quantitative composition of active substances in the same dosage form as the reference drug, and the bioequivalence or therapeutic equivalence of which to the reference drug has been confirmed in relevant studies [4].

One of the main goals of the federal target program “Development of the pharmaceutical and medical industry of the Russian Federation for the period until 2021 and beyond” (Resolution of the Government of the Russian Federation of February 17, 2011 No. 91) is the development and introduction into production of competitive generic drugs [5].

At the moment, the draft order of the Government of the Russian Federation “Strategy for the development of the pharmaceutical industry of the Russian Federation for the period until 2030” has been discussed, providing for an increase in the volume of exports of pharmaceutical products to foreign markets, which presupposes the compliance of innovative and reproduced drugs with international quality standards.

The use of generic drugs is advisable from a therapeutic and economic point of view if they have proven therapeutic equivalence or bioequivalence with respect to the reference drug and have equivalent qualitative and quantitative composition of active substances, composition of excipients, dosage form and route of administration, that is, they are interchangeable [6].

According to Rosstat, diseases of the digestive system rank third among the causes of death in Russia, behind diseases of the circulatory system and malignant neoplasms. A significant proportion of diseases of the gastrointestinal tract (GIT) are acid-dependent diseases (ADDs). The relevance of this problem is due to the widespread prevalence of CVD among the population of all countries (40–50%) and the development of serious complications. Proton pump inhibitors (PPIs), which include rabeprazole, are considered therapeutic leaders for gastrointestinal tract diseases and are mandatory for use in accordance with leading clinical guidelines [7–13].

PPIs are prodrugs, the modification of which into a drug occurs in the acidic environment of the stomach [14, 15]. The highest rate of onset of the antisecretory effect is characteristic of rabeprazole, which has been proven in numerous studies [16–22] and is explained by a number of properties of the drug. The highest value of the ionization constant (pKa) of rabeprazole compared to other substances determines faster transformation and a high rate of its accumulation in the tubules of parietal cells. The pKa value also affects the stability of the molecule in an acidic environment. Rabeprazole is the least stable under these conditions, as a result of which it is easily activated both at low and at fairly high pH levels. A unique feature of the drug is its metabolism, which is minimally associated with the cytochrome system CYP2C19 and CYP3A4. The main route of metabolism is non-enzymatic reduction to thioester, which provides a stable antisecretory effect regardless of what type of metabolizer the patients are [23, 24], and also minimizes the risk of pharmacokinetic interactions with other drugs [25].

Rabeprazole preparations are widely represented on the Russian pharmaceutical market. Thus, currently 13 generic drugs are registered in the form of solid dosage forms containing rabeprazole sodium as the active ingredient [26]. The study of the interchangeability of these generic drugs relative to the reference one is of particular interest, due to the significant effectiveness and safety of rabeprazole, proven in numerous studies [27–30].

According to WHO, from 10 to 20% of reproduced drugs do not pass quality control testing, which may be due to the poor quality of the original substances, modifications of the technological process and other pharmaceutical factors that determine the properties of the finished drug [31]. Thus, the study of the interchangeability of drugs is relevant and can largely influence the increase in the effectiveness and safety of pharmacotherapy.

An alternative to time-consuming and costly in vivo

To determine the bioequivalence of reproduced drugs, the introduction of comparative
in vitro
using the “biowaiver” procedure may be possible.

Biowaiver _

) - a procedure according to which the determination of interchangeability and registration of generic drugs is carried out on the basis of their biopharmaceutical properties (according to the biopharmaceutical classification system (BCS)) and
in vitro

in vitro
methods
in
bioequivalence studies vivo .
According to the position of the EMA [12, 32], WHO [20] and the US Food and Drug Administration (FDA) [11], confirmation of the bioequivalence of pharmaceutically equivalent or alternative drugs in one of the options may be obtained from comparative in vitro
.
The concept of “biowaiver” is used in Russian regulatory documents as a replacement for a bioequivalence study with a comparative dissolution kinetics test (CDKT) [3]. According to the literature [33–36], in comparative studies of in vitro
the authors established the equivalence of a number of reproduced drugs of various pharmacological groups to the reference drug, which can serve as a basis for recognizing these drugs as interchangeable in accordance with foreign legislation.

Purpose

This study is to assess the
in vitro
of rabeprazole preparations presented on the Russian pharmaceutical market according to TSCR.

Material and methods

The object of the study was rabeprazole drugs presented on the pharmaceutical market of St. Petersburg - enteric-coated tablets and capsules containing 20 mg of active pharmaceutical substance (API). Six different generic drugs, named R1, R2, R3, R4, R5, R6, were compared with the original drug rabeprazole (R) using TSKR.

In vitro equivalence

were assessed based on the Guidelines for the Examination of Drugs [32] in 900 ml media with different pH values: HCl 0.1 M (pH 1.2) and phosphate buffer solutions (PBS) (pH 6.8 and 4.5). The test was carried out on 12 units of each drug using the “RC-6 Dissolution Tester” device (China), “Paddle mixer” apparatus.

Statistical data processing was carried out using Microsoft Office Excel at a confidence level of P = 95% and the corresponding Student coefficients (tp) according to the State Pharmacopoeia of the Russian Federation, XIV edition (SP XIV), volume 1.

Research results

Rabeprazole sodium, a substituted benzimidazole salt, is a white or slightly yellowish-white substance, very soluble in water and methanol, soluble in ethanol, chloroform and ethyl acetate, insoluble in ether and n-hexane. According to the BCS, rabeprazole belongs to class I or III due to its high solubility, which makes it possible to carry out TSCR for this API.

In accordance with the requirements of Global Fund XIV, enteric dosage forms must be resistant to the effects of gastric juice and release the active substance in the intestinal juice [37].

All studied drugs met the quality requirements in terms of “dissolution” according to “GPM.1.4.1.0015.18 Tablets”, “GPM.1.4.1.0005.18 Capsules” and “GPM.1.4.2.0014.15 Dissolution for solid dosage forms” ( GF XIV, volume 2). At the same time, it was found that the release of rabeprazole from the studied drugs in an environment with pH 6.8 occurred at different rates (Fig. 1). Thus, the substance from capsules (R3 and R4) passed into the dissolution medium faster compared to tablets, which is associated with a higher rate of dissolution of the hard gelatin shell of the capsules. The difference in the rate of release of rabeprazole from drug R2 is apparently due to the presence of two disintegrants (methylcellulose and carboxymethylcellulose) in combination with starch.

In an environment with pH 4.5, the release of the active substance was observed only from drug R2 (Fig. 2), which can be explained by the presence of polysorbate-80 in the enteric coating of this drug, which improves the wettability and water permeability of the dosage form [38].

In a dissolution medium with pH 1.2, simulating gastric juice, the amount of API released from all studied drugs did not exceed 3% (Fig. 3).

The similarity of the dissolution profiles of rabeprazole from 20 mg tablets and capsules in different media was confirmed by calculating the similarity coefficients f2, the values ​​of which should be in the range of 50–100 (table). Thus, in a medium of 0.1 M HCl pH 1.2, all studied rabeprazole drugs turned out to be similar to the reference drug. The values ​​of similarity coefficients in a medium with pH 4.5 indicate the equivalence of five drugs (R1, R3, R4, R5 and R6) to the reference drug, while in a medium with pH 6.8 similarity was established only for two drugs (R1 and R5) .

When assessing the biological equivalence of rabeprazole preparations according to TSKR in vitro

The similarity of the dissolution profiles of rabeprazole sodium from drugs R1 and R5 was established, which suggests their bioequivalence to the reference drug Pariet. Other studied drugs are not equivalent to the original drug in all environments, so we cannot speak with confidence about their bioequivalence.

Discussion

The main trend of the Russian pharmaceutical market over recent years has been the switching of consumers to generic drugs. According to the analytical report of DSM Group, according to the results of the first nine months of 2021, the share of original drugs decreased by 1.1% in rubles and by 0.6% in units compared to the same period last year. At the same time, there is a significant predominance of the group of generic drugs - 62.7% in value terms and 84.4% in physical terms. According to forecasts, the numbers will increase (Fig. 4) [2].

As already noted, the cost of generic drugs is usually lower than original drugs, which is explained by the lack of manufacturer costs for the search and development of APIs, dosage forms, conducting full-scale clinical trials, as well as advertising and promotion [31].

Not all generic medicinal products fully correspond to the reference drugs. In vitro drug research

according to TSKR can resolve issues of bioequivalence in a relatively short time, at least immediately identify drugs whose properties do not correspond to those of the original drug.

In the above study of various rabeprazole analogues for compliance with the characteristics of the original drug, it was demonstrated that only two of the six reproduced products can fully serve as an alternative to the reference drug.

The rapid solubility of most of the tested drugs in an alkaline environment (pH 6.8), in contrast to the original rabeprazole, will certainly affect the clinical effectiveness of the drugs under conditions of elevated pH values, which is observed, for example, with alkaline reflux.

Thus, the question remains of choosing an adequate replacement of reference drugs based on the results of a bioequivalence study, the first stage of which may be TSKR.

The authors declare no conflict of interest.

Drug interactions

The active substance rabeprazole sodium does not interact with antacids, so it is allowed to be taken together with drugs such as Rennie, Almagel, Phosalugel, etc.

At the same time, rabeprazole can increase the concentration in the blood of substances such as digoxin and ketoconazole. This is important to consider when taking medications with these active ingredients.

Rabeprazole can be taken together with medications such as Theophylline, Phenytonin, Warfarin and Diazepam. The simultaneous use of Pantoprazole is possible.

Rabeprazole-SZ 10 mg

Registration number

LP-003466

Dosage form

enteric capsules

Compound

1 capsule contains:

active substance:

rabeprazole pellets – 118 mg

in terms of rabeprazole sodium – 10 mg

[pellet core: Rabeprazole sodium – 10.00 mg, granulated sugar (sucrose, starch molasses) – 71.47 mg, sodium carbonate – 1.65 mg, talc – 1.77 mg, titanium dioxide – 0.83 mg, hypromellose (hydroxymethylcellulose) – 14.75 mg;

pellet shell: hypromellose phthalate (hydroxypropyl methyl cellulose phthalate) – 15.93 mg, cetyl alcohol – 1.60 mg]

Excipients:

Hard gelatin capsules No. 3

Body: titanium dioxide – 2.0%, gelatin – up to 100%

Cap: azorubine dye (carmazine dye) – 0.6619%, indigo carmine – 0.0286%, titanium dioxide – 0.6666%, gelatin – up to 100%

Description

Hard gelatin capsules No. 3, white body with a dark red cap. The contents of the capsules are spherical pellets from almost white to white with a creamy or yellowish tint.

ATX code

[A02BC04]

Pharmacological properties

Pharmacodynamics

Mechanism of action

Rabeprazole sodium belongs to the class of antisecretory substances, benzimidazole derivatives. Suppresses the secretion of gastric juice by specifically inhibiting H+/K+-ATPase on the secretory surface of gastric parietal cells. 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, regardless of the stimulus.

Rabeprazole sodium does not have anticholinergic properties.

Antisecretory action

After oral administration of 20 mg of rabeprazole sodium, the antisecretory effect develops within an hour. Inhibition of basal and stimulated acid secretion 23 hours after taking the first dose of rabeprazole sodium is 69% and 82%, respectively, and lasts up to 48 hours. This duration of pharmacodynamic action far exceeds that predicted by the half-life (approximately one hour). This effect can be explained by the prolonged binding of the drug to the H+/K+-ATPase of gastric parietal cells. The magnitude of the inhibitory effect of rabeprazole sodium on acid secretion reaches a plateau after three days of taking rabeprazole sodium. When you stop taking it, secretory activity is restored within 1-2 days.

Effect on plasma gastrin levels

In clinical studies, patients took 10 or 20 mg of rabeprazole sodium daily for treatment durations of up to 43 months. Plasma gastrin levels were elevated in the first 2–8 weeks, reflecting an inhibitory effect on acid secretion. Gastrin concentrations returned to baseline levels usually within 1-2 weeks after cessation of treatment.

Effect on enterochromaffin-like cells

In a study of human gastric biopsy specimens from the antrum and fundus of the stomach of 500 patients treated with rabeprazole sodium or a comparator for 8 weeks, persistent changes in the morphological structure of enterochromaffin-like cells, severity of gastritis, incidence of atrophic gastritis, intestinal metaplasia, or prevalence of Helicobacter infection pylori were not detected.

In a study of 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 have been no reported 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 currently been detected. It has been shown that rabeprazole sodium, when taken orally at a dose of 20 mg for 2 weeks, does not affect the function of the thyroid gland, carbohydrate metabolism, the level of parathyroid hormone in the blood, as well as the levels of cortisol, estrogens, testosterone, prolactin, glucagon, follicle-stimulating hormone (FSH), luteinizing hormone (LH), renin, aldosterone and growth hormone.

Pharmacokinetics

Absorption

Rabeprazole is rapidly absorbed from the intestine and peak plasma concentrations are achieved approximately 3.5 hours after a 20 mg dose. Changes in peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) of rabeprazole are linear in the dose range from 10 to 40 mg. Absolute bioavailability after oral administration of 20 mg (compared to intravenous administration) is approximately 52%. In addition, bioavailability does not change with repeated dosing of rabeprazole. In healthy volunteers, the plasma half-life is approximately 1 hour (ranging 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 is doubled compared to healthy volunteers, indicating a decrease in first-pass metabolism, and the plasma half-life is increased by 2 to 3 times. Neither the time of taking the drug during the day nor antacids affect the absorption of rabeprazole. Taking the drug with fatty foods slows down the absorption of rabeprazole by 4 hours or more, but neither Cmax nor the degree of absorption changes.

Distribution

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 14C-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: a conjugate of mercapturic acid (M5) and carboxylic acid (M6), as well as in the form of two unknown metabolites identified during toxicological analysis.

The remainder of the rabeprazole taken is excreted in the feces.

The total elimination is 99.8%. These data indicate a small excretion of rabeprazole metabolites in bile. The main metabolite is thioester (M1). The only active metabolite is desmethyl (M3), but this was observed at low concentrations in only one study participant after taking 80 mg rabeprazole.

End stage renal failure

In patients with stable end-stage renal disease who require maintenance hemodialysis (creatinine clearance <5 ml/min/1.73 m2), the elimination of rabeprazole is similar to that of healthy volunteers. AUC and Cmax in these patients were approximately 35% lower than in healthy volunteers. The average half-life of rabeprazole was 0.82 hours in healthy volunteers, 0.95 hours in patients undergoing 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 liver cirrhosis tolerate rabeprazole 20 mg once daily, although AUC is doubled and Cmax is increased by 50% compared to sex-matched healthy volunteers.

Elderly patients

In elderly patients, the elimination of rabeprazole is somewhat slower. After 7 days of taking rabeprazole 20 mg per day in elderly patients, AUC was approximately twice as high and 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 metabolism of CYP2C19, after 7 days of taking rabeprazole at a dose of 20 mg per day, AUC increases by 1.9 times, and the half-life increases by 1.6 times compared with the same parameters in “rapid metabolizers,” while Cmax increases by 40%.

Indications for use

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

Contraindications

• hypersensitivity to rabeprazole, substituted benzimidazoles or to the auxiliary components of the drug;
• sucrase/isomaltase deficiency, fructose intolerance, glucose-galactose deficiency;
• pregnancy;
• breastfeeding period;
• children under 18 years of age.

Carefully

• severe renal failure;
• severe liver failure.

Use during pregnancy and breastfeeding

There are no data on the safety of rabeprazole during pregnancy.

Reproduction studies in rats and rabbits showed no evidence of impaired fertility or fetal developmental defects associated with rabeprazole; however, in rats the drug crosses the placental barrier in small quantities. Rabeprazole-SZ should not be used during pregnancy.

It is not known whether rabeprazole is excreted in breast milk.

Appropriate studies on the use of the drug during breastfeeding have not been conducted.

However, rabeprazole was found in the milk of lactating rats, and therefore Rabeprazole-SZ should not be used by women during breastfeeding.

Directions for use and doses

Orally, at a dose of 10 mg once a day.

Rabeprazole-SZ capsules should be swallowed whole. It is recommended to take the drug in the morning, before meals. It has been established that neither time of day nor food intake affects the activity of rabeprazole sodium, but the recommended time of taking Rabeprazole-SZ capsules contributes to better patient compliance with the treatment regimen.

If there is no effect during the first three days of treatment, examination by a specialist is necessary. The maximum course of treatment without consulting a doctor is 14 days.

Side effect

Based on the experience of clinical studies, we can conclude that the drug Rabeprazole-SZ is usually well tolerated by patients. Side effects, generally mild or moderate, are transient.

During clinical studies, the following adverse reactions were observed when taking rabeprazole: headache, abdominal pain, diarrhea, flatulence, constipation, dry mouth, dizziness, rash, peripheral edema.

Adverse reactions are systematized in accordance with the WHO Classification:

Very common (≥ 1/10);

Often (≥ 1/100, < 1/10);

Uncommon (≥ 1/1000, < 1/100);

Rarely (≥ 1/10000, < 1/1000);

Very rare (<1/10000), including isolated cases;

Frequency unknown (cannot be determined from available data).

Disorders of the blood and lymphatic system: rarely - thrombocytopenia, neutropenia, leukopenia;

Immune system disorders: rarely - acute systemic allergic reactions;

Metabolic and nutritional disorders: rarely – hypomagnesemia;

Disorders of the liver and biliary tract: increased activity of liver enzymes, rarely - hepatitis, jaundice, hepatic encephalopathy;

Disorders of the skin and subcutaneous tissues: rarely - bullous rashes, urticaria; very rarely - erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome;

Musculoskeletal and connective tissue disorders: rarely – myalgia, arthralgia;

Renal and urinary tract disorders: very rarely – interstitial nephritis;

Disorders of the genital organs and breast: very rarely - gynecomastia.

No changes in other laboratory parameters were observed while taking rabeprazole sodium.

According to post-marketing observations, when taking proton pump inhibitors (PPIs), there may be an increased risk of fractures, subacute cutaneous lupus erythematosus and glandular polyps of the fundus of the stomach (see section "Special Instructions"). Rare reports of hepatic encephalopathy have been reported in patients with cirrhosis.

Overdose

Symptoms

Data on intentional or accidental overdose are minimal. There have been no cases of severe overdose of rabeprazole.

Treatment

A specific antidote for rabeprazole is unknown. Rabeprazole binds well to plasma proteins and is therefore poorly excreted during dialysis. In case of overdose, symptomatic and supportive treatment should be provided.

Interaction with other drugs

Cytochrome 450 system

Rabeprazole sodium, like other proton pump inhibitors (PPIs), 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 isoenzymes CYP2C19 and CYP3A4.

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 whether patients metabolize diazepam extensively or poorly).

A study of combination therapy with antibacterial drugs was conducted. This four-way crossover study involved 16 healthy volunteers who received rabeprazole 20 mg, amoxicillin 1000 mg, clarithromycin 500 mg, or a combination of these three drugs (RAC - rabeprazole, amoxicillin, clarithromycin). AUC and Cmax values ​​for clarithromycin and amoxicillin were similar when combination therapy was compared with monotherapy. AUC and Cmax for rabeprazole increased by 11% and 34%, respectively, and for 14-hydroxyclarithromycin (the active metabolite of clarithromycin), AUC and Cmax increased by 42% and 46%, respectively, for combination therapy compared with monotherapy. This increase in exposure rates for rabeprazole and clarithromycin was not considered clinically significant.

Interactions due to inhibition of gastric acid secretion

Rabeprazole sodium provides a stable and long-lasting suppression of gastric acid secretion. Thus, interactions may occur with substances for which absorption is pH dependent. When taken simultaneously with rabeprazole sodium, the absorption of ketoconazole is reduced by 30%, and the absorption of digoxin is increased by 22%. Therefore, some patients should be monitored to determine whether dose adjustments are necessary when taking rabeprazole sodium concomitantly with ketoconazole, digoxin, or other drugs for which absorption is pH dependent.

Atazanavir

When atazanavir 300 mg/ritonavir 100 mg was coadministered with omeprazole (40 mg once daily) or atazanavir 400 mg with lansoprazole (60 mg once daily) in healthy volunteers, a significant reduction in atazanavir exposure was observed. Absorption of atazanavir is pH dependent. Although concomitant use with rabeprazole has not been studied, similar results are expected for other proton pump inhibitors. Therefore, concomitant use of atazanavir with proton pump inhibitors, including rabeprazole, is not recommended.

Antacids

In clinical studies, antacid substances were used in conjunction with rabeprazole sodium. Clinically significant interactions of rabeprazole sodium with aluminum hydroxide gel or magnesium hydroxide were not observed.

Eating

In a clinical study, no clinically significant interactions were observed when rabeprazole sodium was taken with a low-fat meal. Taking rabeprazole sodium simultaneously with a fat-enriched meal may slow down the absorption of rabeprazole by up to 4 hours or more, however, Cmax and AUC do not change.

Cyclosporine

In vitro experiments using human liver microsomes showed that rabeprazole inhibits the metabolism of cyclosporine with an IC50 of 62 µM, i.e. at a concentration 50 times higher than the Cmax for healthy volunteers after 14 days of taking 20 mg rabeprazole. The degree of inhibition is similar to that of omeprazole for equivalent concentrations.

Methotrexate

Adverse event reports, published pharmacokinetic studies, and retrospective analyzes suggest that concomitant use of PPIs and methotrexate (primarily at high doses) may result in increased concentrations of methotrexate and/or its metabolite hydroxymethotrexate and prolong the elimination half-life. However, no specific drug interaction studies have been conducted between methotrexate and PPIs.

Impact on laboratory results

The use of PPIs leads to a decrease in gastric acidity, which can lead to an increase in chromogranin A (CgA) in the blood serum. Elevated CgA levels may lead to misinterpretation of laboratory results for the presence of a neuroendocrine tumor. To avoid this effect, use of Rabeprazole-SZ should be temporarily discontinued at least 14 days before assessing CgA levels; repeating the test should be considered if the initial CgA level is high.

special instructions

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

Rabeprazole-SZ capsules should be swallowed whole. It has been established that neither time of day nor food intake affects the activity of rabeprazole sodium.

In a special study in patients with mild or moderate liver dysfunction, there was no significant difference in the incidence of side effects of rabeprazole sodium from that of healthy individuals matched by sex and age, but despite this, caution is recommended when first prescribing Rabeprazole-SZ to patients with severe liver dysfunction. The AUC of rabeprazole sodium in patients with severe hepatic impairment is approximately two times higher than in healthy patients.

For patients with impaired renal or liver function, dose adjustment of Rabeprazole-SZ is not required.

Hypomagnesemia

Rare cases of symptomatic or asymptomatic hypomagnesemia have been reported when treated with PPIs for at least 3 months. In most cases, these reports were received one year after therapy. Serious adverse events included tetany, arrhythmia, and seizures. Most patients required treatment for hypomagnesemia, including magnesium replacement and discontinuation of PPI therapy. In patients who will be receiving long-term treatment or who are taking PPIs with drugs such as digoxin or drugs that can cause hypomagnesemia (eg, diuretics), health care providers should monitor magnesium levels before initiating PPI treatment and during treatment.

Patients should not take other acid-reducing agents, such as H2 receptor blockers or proton pump inhibitors, at the same time as Rabeprazole-SZ.

Bone fractures

Observational studies suggest that proton pump inhibitor (PPI) therapy may increase the risk of osteoporosis-related fractures of the hip, wrist, or spine. The risk of fractures was increased in patients receiving high doses of PPIs for a long time (a year or more).

Concomitant use of rabeprazole with methotrexate

According to the literature, simultaneous use of PPIs with methotrexate (primarily in high doses) can lead to increased concentrations of methotrexate and/or its metabolite hydroxymethotrexate and increase the half-life, which can lead to methotrexate toxicity. If high doses of methotrexate are required, temporary discontinuation of PPI therapy may be considered.

Clostridium difficile.

PPI therapy may lead to an increased risk of gastrointestinal infections such as Clostridium difficile.

Subacute cutaneous lupus erythematosus (SCLE)

There are reports of cases of PCLE during PPI therapy. If skin lesions appear, especially on areas of skin exposed to direct sunlight, and are accompanied by arthralgia, the patient should immediately seek medical attention and the health care professional should decide to discontinue rabeprazole therapy. The occurrence of PCLE with previous PPI therapy may increase the risk of PCLE with other PPIs.

Glandular polyps of the fundus of the stomach

Long-term use of PPIs, including rabeprazole, appears to be associated with an increased risk of fundal glandular polyps. Most glandular polyps of the fundus of the stomach are asymptomatic. Patients with large or ulcerated polyps may be at risk for gastrointestinal bleeding or small bowel obstruction. The dosage and duration of PPI therapy for such patients should be kept to a minimum.

Patients taking Rabeprazole-SZ for short-term symptomatic treatment of manifestations of GERD and NERD (for example, heartburn) without a prescription should consult a doctor in the following cases:

• using medications to relieve symptoms of heartburn and indigestion for 4 weeks or more,
• the appearance of new symptoms or a change in previously observed symptoms in patients over 55 years of age,
• cases of unintentional weight loss, anemia, bleeding in the gastrointestinal tract, dysphagia, pain when swallowing, persistent vomiting or vomiting with blood and epigastric contents, cases of stomach ulcers or a history of gastric surgery, jaundice, etc. (including impaired liver and kidney function).

Patients suffering from recurring symptoms of indigestion or heartburn for a long time should be monitored regularly by a doctor. Patients over 55 years of age who take over-the-counter medications daily to relieve symptoms of heartburn and indigestion should tell their healthcare provider.

Patients should not take other acid-reducing agents, such as H2 receptor blockers or proton pump inhibitors, at the same time as Rabeprazole-SZ.

If using other medications, patients should consult their pharmacist or healthcare provider before starting therapy with the over-the-counter Rabeprazole-SZ drug.

Patients should inform their physician before using Rabeprazole-SZ without a prescription if they are scheduled for an endoscopic examination.

Avoid taking Rabeprazole-SZ before performing a urea breath test.

Patients with severe hepatic impairment should consult a physician before initiating over-the-counter Rabeprazole-SZ therapy for short-term symptomatic treatment of manifestations of GERD and NERD (eg, heartburn).

Impact on the ability to drive vehicles and operate machinery

Based on the pharmacodynamics of rabeprazole sodium and its profile of undesirable effects, it is unlikely that Rabeprazole-SZ affects the ability to drive vehicles and operate machinery. However, if drowsiness occurs, these activities should be avoided.

Release form

Enteric capsules 10 mg.

10 or 14 capsules per blister pack.

30, 60 or 100 capsules per polymer jar or polymer bottle.

Each jar or bottle, 2, 3, 6 blister packs of 10 capsules each, 1, 2, 4 blister packs of 14 capsules, together with instructions for use, are placed in a cardboard box.

Best before date

3 years.

Do not use after the expiration date stated on the package.

Storage conditions

In a place protected from light, at a temperature not exceeding 25 ° C.

Vacation conditions

Available without a prescription.

Prescription drug

Over-the-counter drug

special instructions

The course of treatment with Rabeprazole should begin with a check of the gastrointestinal tract. If malignant tumors are detected, you should not take the drug, since the medicine masks some of the symptoms of cancer. This can make them difficult to diagnose and treat because time will be lost.

The drug should be taken with caution in cases of diagnosed liver disease. If taken simultaneously with Digoxin and Ketonazole, the dosage of these drugs must be adjusted.

One of the possible side effects of Rabeprazole is increased fatigue and drowsiness. Therefore, drivers and operators of moving machinery should take the product with caution. During therapy, you may have to temporarily give up work that requires increased concentration.

Rabeprazole, 20 mg, enteric tablets, 14 pcs.

Before and after treatment, endoscopic monitoring is required to exclude malignant neoplasms, because Treatment may mask symptoms and delay correct diagnosis.

Rabeprazole tablets should not be chewed or crushed. The tablets should be swallowed whole. It has been established that neither time of day nor food intake affects the activity of rabeprazole.

In a special study in patients with mild or moderate hepatic impairment, the incidence of side effects of rabeprazole was not found to be significantly different from that in age- and sex-matched healthy individuals, but despite this, caution is recommended when first prescribing the drug to patients with severe impairment. liver.

For patients with impaired renal or hepatic function, dosage adjustment of rabeprazole is not required. The AUC of rabeprazole sodium in patients with severe hepatic impairment is approximately two times higher than in healthy patients.

Hypomagnesemia

Rare cases of symptomatic or asymptomatic hypomagnesemia have been reported when treated with PPIs for at least 3 months. In most cases, these reports were received one year after therapy. Serious adverse events included tetany, arrhythmia, and seizures. Most patients required treatment for hypomagnesemia, including magnesium replacement and PPI discontinuation. In patients who will be receiving long-term treatment or who are taking PPIs with drugs such as digoxin or drugs that can cause hypomagnesemia (eg, diuretics), health care providers should monitor magnesium concentrations before initiating PPI treatment and during treatment.

Patients should not take other acid-reducing agents, such as H2-histamine blockers or proton pump inhibitors, at the same time as rabeprazole.

Bone fractures

PPI therapy may increase the risk of osteoporosis-related fractures of the hip, wrist, or spine. The risk of fractures is increased in patients receiving high doses of PPIs for a long time (a year or more).

Concomitant use of rabeprazole with methotrexate

According to the literature, simultaneous use of PPIs with methotrexate (primarily in high doses) can lead to increased concentrations of methotrexate and/or its metabolite hydroxymethotrexate and increase the half-life. which can lead to methotrexate toxicity. If high doses of methotrexate are required, temporary discontinuation of PPI therapy may be considered.

Infections caused by Salmonella, Campylobacter and Clostridium difficile

PPI therapy may lead to an increased risk of gastrointestinal infections, such as those caused by Salmonella, Campylobacter, and Clostridium difficile.

Impact on the ability to drive vehicles and operate machinery

Based on the pharmacodynamics of rabeprazole and its profile of undesirable effects, it is unlikely that rabeprazole affects the ability to drive vehicles and machinery. However, if drowsiness occurs, these activities should be avoided.