Rabimac enteric-coated tablets 20 mg blister No. 30

Instructions Rabimac enteric-coated tablets 20 mg blister No. 30

Composition

active ingredient: rabeprazole;

1 tablet contains rabeprazole sodium 20 mg;

Excipients: 20 mg tablets: mannitol (E 421), low-substituted hydroxypropylcellulose, heavy magnesium oxide, povidone, sodium hydroxide, talc, magnesium stearate, ethylcellulose, yellow iron oxide (E 172), titanium dioxide (E 171), methacrylate copolymer dispersion, triethyl citrate.

Dosage form

The film-coated tablets are enteric-coated.

Main physicochemical properties:

20 mg tablets: round, biconvex, film-coated, enteric-coated tablets, yellow in color, smooth on both sides.

Pharmacotherapeutic group

Drugs affecting the digestive tract and metabolism. Drugs for the treatment of diseases associated with acidity disorders. Antiulcer drugs and drugs for the treatment of gastroesophageal reflux. Proton pump inhibitors. Rabeprazole. ATC code A02B C04.

Pharmacological properties

Pharmacodynamics

Mechanism of action. Rabeprazole sodium belongs to the class of antisecretory compounds, substituted benzimidazoles, does not have anticholinergic properties and is not an antagonist of histamine H2 receptors, but inhibits gastric acid secretion by specific inhibition of the enzyme H+/K+-ATPase on the secretory surface of the gastric parietal cells (acid or proton pump). The effect is dose-dependent and leads to inhibition of both basal and stimulated acid secretion, regardless of the stimulus. Animal studies have shown that after administration, rabeprazole sodium rapidly disappears from both blood plasma and the gastric mucosa. Rabeprazole sodium has weak alkaline properties, is rapidly absorbed and concentrated in parietal cells at all dosages. Rabeprazole sodium is converted to the active sulfenamide form by protonation and thus reacts with available cysteine residues of the proton pump.

Antisecretory activity. After oral administration of 20 mg of rabeprazole sodium, the antisecretory effect is observed after 1 hour and reaches a maximum after 2-4 hours. The effect of inhibition of basal function and stimulation of food secretion of acid 23 hours after taking the first dose of rabeprazole sodium was 69 and 82%, respectively, and the duration of this effect reached 48 hours. The effectiveness of rabeprazole sodium in inhibiting acid secretion is somewhat enhanced during daily administration of 1 tablet, but stable inhibition of secretion is achieved 3 days after the start of taking this drug. After stopping taking rabeprazole sodium, secretory activity normalizes within 2-3 days.

Reducing stomach acidity, regardless of any factors, including proton pump inhibitors such as rabeprazole, increases the number of bacteria in the gastrointestinal tract. Treatment with proton pump inhibitors may increase the risk of gastrointestinal infections such as Salmonella, Campylobacter, and Clostridium difficile.

Effect on serum gastrin concentrations. After administration of 10 or 20 mg rabeprazole sodium once daily for 43 months, serum gastrin concentrations increased during the first 2-8 weeks of therapy, reflecting inhibition of acid secretion. Gastrin concentrations returned to baseline levels, usually within 1-2 weeks after discontinuation of treatment.

Examination of gastric fundus and antrum biopsies from a large number of patients treated with rabeprazole or comparator for 8 weeks revealed no histological changes, no significant gastritis, no increased incidence of atrophic gastritis, no intestinal metaplasia, and no spread of H. pylori infection. No significant changes in these tests were observed during long-term treatment for 36 months.

Other effects. There are currently no data on systemic effects on the central nervous system (CNS), cardiovascular and respiratory systems caused by the use of rabeprazole sodium. Oral administration of 20 mg of rabeprazole sodium per day for 2 weeks does not affect thyroid function, carbohydrate metabolism, as well as blood concentrations of parathyroid hormone, cortisone, estrogen, testosterone, prolactin, cholecystokinin, secretin, glucagon, follicle-stimulating hormone (FSH), luteinizing hormone (LH), renin, aldosterone and somatotropic hormone.

Studies have shown no clinically significant interactions between rabeprazole and amoxicillin.

Rabeprazole has no negative effect on the plasma levels of amoxicillin and clarithromycin when used concomitantly for the eradication of H. pylori infection in the upper gastrointestinal tract.

Absorption. Rabimac is an enteric-coated tablet. Absorption of rabeprazole sodium begins only after the tablet has passed the stomach. Rabeprazole sodium is rapidly absorbed from the intestine. Peak plasma concentrations of rabeprazole are reached approximately 3.5 hours after a 20 mg dose. 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 about 52%, mainly due to first-pass metabolism. In addition, bioavailability does not increase with repeated administration of rabeprazole sodium. The plasma elimination half-life was approximately 1 hour (range 0.7 to 1.5 hours), and the total clearance was estimated to be 283±98 mL/min.

Distribution: In humans, the degree of binding of rabeprazole sodium to blood plasma proteins is approximately 97%.

Metabolism and Excretion: Like other members of the proton pump inhibitor class, rabeprazole is metabolized by the cytochrome P450 (CYP450) hepatic drug metabolism system. In vitro studies with human liver microsomes have shown that rabeprazole sodium is metabolized by CYP450 isoenzymes (CYP2C19 and CYP3A4). At the expected human plasma levels, rabeprazole does not induce or inhibit CYP3A4. However, in vitro studies cannot always be extrapolated to in vivo situations; these results indicate that an interaction between rabeprazole and cyclosporine is not expected. In humans, the major metabolites present in plasma are the thioester (M1) and the carboxylic acid (M6), while minor metabolites present in low concentrations are the sulfone (M2), dimethylthioester (M4), and mercapturic acid conjugate (M5). Only the dimethyl metabolite (M3) has minor antisecretory activity, but it is not present in plasma.

After a single dose of 20 mg of 14C-labeled rabeprazole sodium, unchanged rabeprazole was not detected in the urine. Approximately 90% of the dose was eliminated in the urine, mainly as two metabolites: the mercapturic acid conjugate (M5) and the carboxylic acid (M6); in addition, two unidentified metabolites were found in toxicological studies in laboratory animals. The remaining part of the dose was found in the feces.

Gender: Since a single dose of 20 mg of rabeprazole sodium is adjusted for body weight and height, gender does not affect pharmacokinetic parameters.

Renal impairment. In patients with end-stage renal disease undergoing maintenance haemodialysis (creatinine clearance <5 ml/min/1.73 m2), the disposition of rabeprazole sodium was very similar to that in healthy volunteers. Rabeprazole sodium AUC and Cmax in these patients were increased by almost 35% compared to those in healthy volunteers. The mean half-life was 0.82 hours in healthy volunteers, 0.95 hours in haemodialysis patients and 3.6 hours in post-dialysis patients. The clearance of the drug in patients with renal failure undergoing haemodialysis was approximately twice that in healthy volunteers.

Hepatic impairment. After a single dose of 20 mg of rabeprazole sodium in patients with moderate chronic liver disease, the AUC increased twofold and the half-life of rabeprazole was two to threefold longer than in healthy volunteers. Thus, with daily administration of 20 mg for 7 days, the AUC should increase by at least 1.5-fold and the change in peak plasma concentrations Cmax should be up to 1.2. The half-life in patients with liver disease was 12.3 hours compared to 2.1 hours in healthy volunteers. The pharmacodynamic response (gastric pH measurement) for the two groups of patients was similar in therapeutic parameters.

Elderly patients. The elimination of rabeprazole sodium is somewhat reduced in elderly patients. After 7 days of rabeprazole sodium 20 mg daily, the AUC in elderly subjects was approximately twice as high, Cmax increased by 60%, and T1/2 increased by 30% compared to those in young healthy volunteers. However, it should be noted that there was no evidence of accumulation of rabeprazole sodium.

CYP2C19 polymorphism: When rabeprazole sodium was administered at a dose of 20 mg per day for 7 days to patients who are CYP2C19 poor metabolisers, AUC and half-life were approximately 1.9 and 1.6 times higher, respectively, compared to those in extensive metabolisers; however, Cmax was only increased by 40%.

Indication

Active duodenal peptic ulcer; active benign gastric ulcer; erosive or ulcerative gastroesophageal reflux disease (GERD); long-term treatment of gastroesophageal reflux disease (GERD maintenance therapy); symptomatic treatment of moderate to very severe gastroesophageal reflux disease (GERD symptomatic treatment); Zollinger-Ellison syndrome; in combination with appropriate antibacterial therapeutic regimens for the eradication of Helicobacter pylori (H. pylori) in patients with gastric and duodenal peptic ulcer.

Contraindication

The drug is contraindicated in patients with hypersensitivity to rabeprazole sodium, substituted benzimidazoles or any other ingredient of the drug. Pregnancy or breastfeeding.

Interaction with other medicinal products and other types of interactions

CYP450 system

Rabeprazole sodium is metabolized by the CYP450 hepatic enzyme system, namely CYP2C19 and CYP3A4.

Studies have found that rabeprazole sodium has no pharmacokinetic or clinically significant interactions with warfarin, phenytoin, theophylline, or diazepam, each of which is metabolized by CYP450.

Interactions caused by inhibition of gastric acid secretion

Rabeprazole sodium causes a strong and prolonged decrease in gastric acid production. Thus, rabeprazole may interact with drugs whose absorption depends on the pH of the gastric contents. Simultaneous use of rabeprazole sodium and ketoconazole or itraconazole may lead to a decrease in the concentration of the latter in the blood plasma, and use with digoxin may lead to an increase in the concentration of the latter. Therefore, individual patients who use these drugs together with Rabimac should be under the supervision of a physician to determine the need for dose adjustment.

Antacids

During clinical trials, patients simultaneously with Rabimac took antacids as needed; in a special study, no interaction of the drug with antacids such as aluminum or magnesium hydroxide was observed.

Atazanavir

Co-administration of atazanavir 300 mg/ritonavir 100 mg with omeprazole (40 mg once daily) or atazanavir 400 mg with lansoprazole (60 mg once daily) in healthy volunteers resulted in a significant decrease in atazanavir exposure. Absorption of atazanavir is pH dependent. Although not studied, similar results are expected with other proton pump inhibitors. Proton pump inhibitors, including rabeprazole, should not be used in combination with atazanavir.

Methotrexate

Adverse reaction reports, published data from population pharmacokinetic studies and retrospective analyses suggest that concomitant use of methotrexate and proton pump inhibitors (mainly at high doses) may lead to increased serum levels of methotrexate and/or its metabolite hydroxymethotrexate. Although no formal studies have been performed.

Clopidogrel

Concomitant administration of clopidogrel and rabeprazole to healthy volunteers had no clinically significant effect on the concentrations of the active metabolite of clopidogrel. No dose adjustment is required.

Food

Studies have shown that the consumption of a low-fat meal does not affect the absorption of rabeprazole sodium. Taking rabeprazole sodium with a fatty meal may delay absorption by 4 hours or more, but the maximum concentration and extent of absorption remain unchanged.

Cyclosporine

In vitro studies have shown that rabeprazole sodium inhibits the metabolism of cyclosporine. This level of inhibition is similar to that of omeprazole.

Drugs not recommended for concomitant use with rabeprazole

Medications that should be prescribed with caution

Application features

Caution should be exercised when prescribing rabeprazole to patients with known hypersensitivity to the drug. The risk of cross-hypersensitivity with other proton pump inhibitors or substituted benzimidazoles cannot be excluded.

Use in elderly patients

Rabeprazole is metabolized exclusively in the liver. Since physiological liver function may decline with age, elderly patients may experience adverse reactions. Therefore, elderly patients should be monitored and recommendations regarding dosage and duration of treatment should be followed.

Symptomatic improvement from treatment with rabeprazole does not exclude the presence of a malignant tumor of the stomach or esophagus, therefore, before prescribing rabeprazole, the presence of a malignant tumor should be excluded.

The risk of cross-hypersensitivity reactions when used with other proton pump inhibitors or substituted benzimidazoles cannot be excluded.

Patients should be warned that Rabimac tablets should not be chewed or crushed, but should be swallowed whole.

Rabeprazole is not recommended for use in children, as there is no experience with its use in this category of patients.

Blood abnormalities (thrombocytopenia and neutropenia) have been reported. In most cases, no other etiology was found; the blood abnormalities were uncomplicated and resolved after discontinuation of rabeprazole.

Liver enzyme abnormalities have been observed both in clinical trials and during the post-marketing period. In most cases, no other etiology was found; the abnormalities were uncomplicated and resolved after discontinuation of rabeprazole.

In studies in patients with mild or moderate hepatic impairment, no significant difference in the incidence of adverse events was observed when taking rabeprazole compared to controls of the same sex and age. The physician should exercise caution when prescribing rabeprazole in the early stages of therapy in patients with severe hepatic impairment, as there are no clinical data on the use of the drug in this group of patients.

The concomitant use of atazanavir and rabeprazole is not recommended (see section 4.5).

Treatment with proton pump inhibitors, including rabeprazole, may increase the risk of gastrointestinal infections such as Salmonella, Campylobacter and Clostridium difficile (see section 5.1).

Proton pump inhibitors, especially when used at high doses and for long periods (more than 1 year), may increase the risk of hip, wrist, and vertebral fractures, especially in elderly patients or in patients with other risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fractures by 10-40%. The risk may also be increased by other factors. Patients at risk of osteoporosis should receive appropriate treatment and take vitamin D and calcium.

Cases of severe hypomagnesemia have been reported in patients taking proton pump inhibitors for at least 3 months, and in most cases for a year. Serious manifestations of hypomagnesemia, such as weakness, tetany, delirium, seizures, dizziness, and ventricular arrhythmias, may occur, but they may occur unexpectedly and go undetected. In most patients, hypomagnesemia resolved after discontinuation of proton pump inhibitors and magnesium replacement therapy.

Patients on long-term concomitant treatment with digoxin or drugs that cause hypomagnesemia (e.g. diuretics) should have their blood magnesium levels monitored before starting and periodically during treatment.

Concomitant use of rabeprazole with methotrexate

Literature data suggest that concomitant use of proton pump inhibitors and methotrexate (mainly at high doses) may increase serum levels of methotrexate and/or its metabolites, which may lead to methotrexate-related toxicity. If high doses of methotrexate are necessary, discontinuation of proton pump inhibitor treatment should be considered.

Effect on vitamin B12 absorption

Rabeprazole sodium, like all drugs that inhibit gastric acid secretion, may reduce the absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be taken into account in patients with reduced body weight or in the presence of risk factors for reduced absorption of vitamin B12 during long-term treatment or in the presence of relevant clinical symptoms.

Subacute cutaneous lupus erythematosus

The use of proton pump inhibitors has been associated with very rare cases of subacute cutaneous lupus erythematosus. If skin lesions, especially in sun-exposed areas, occur, accompanied by arthralgia, the patient should seek medical advice immediately and the doctor should consider discontinuing treatment with the drug. Subacute cutaneous lupus erythematosus after previous treatment with a proton pump inhibitor may increase the risk of subacute cutaneous lupus erythematosus with other PPIs.

Impact on laboratory test results

Elevated chromogranin A (CgA) levels may interfere with the detection of neuroendocrine tumors. To avoid this effect, treatment with the drug should be discontinued at least 5 days before chromogranin levels are measured. If chromogranin and gastrin levels have not returned to the control range after the initial measurement, the measurement should be repeated 14 days after discontinuation of PPI treatment.

Ability to influence reaction speed when driving vehicles or other mechanisms

Given the pharmacodynamics of rabeprazole sodium and its inherent side effect profile, it can be assumed that Rabimac should not adversely affect the ability to drive or use machines. However, in case of drowsiness, it is recommended to avoid driving or using machines.

Use during pregnancy or breastfeeding

Pregnancy

There are no data on the safety of rabeprazole during pregnancy. Reproductive toxicity studies in rats and rabbits have revealed no evidence of impaired fertility or harm to the fetus associated with the use of rabeprazole sodium, although slight placental penetration was observed in rats.

The use of Rabimac during pregnancy is contraindicated.

Breast-feeding

It is not known whether rabeprazole sodium is excreted in human milk. No studies have been conducted. However, rabeprazole sodium is excreted in rat milk.

Rabimac should not be prescribed to women during breastfeeding.

Method of administration and doses

Adults, including elderly patients

Active duodenal peptic ulcer and active benign gastric ulcer: the recommended dose for these conditions is 20 mg once daily in the morning.

In most patients with active duodenal peptic ulcer, the time required for ulcer healing is up to 4 weeks. However, some patients may require an additional 4 weeks of treatment to recover. In most patients with active benign gastric ulcer, healing occurs within 6 weeks, but some patients who are refractory to treatment may require an additional 6 weeks of treatment to heal their ulcers.

Erosive or ulcerative gastroesophageal reflux disease: the recommended dose for these diseases is 20 mg once daily for 4-8 weeks.

Long-term treatment of gastroesophageal reflux disease (GERD maintenance therapy): For long-term treatment, maintenance doses of 10 mg or 20 mg once daily may be used, depending on the patient's clinical response. Symptomatic treatment of moderate to very severe GERD: In patients without esophagitis, the drug should be prescribed at a dose of 10 mg once daily. If symptoms persist after 4 weeks of treatment, the patient should be re-evaluated. Once symptoms have resolved, further control of symptoms can be achieved using an "on-demand" regimen: 10 mg once daily as needed.

Zollinger-Ellison syndrome:

The recommended initial dose is 60 mg once daily. The dose may be gradually increased to 120 mg daily if clinically indicated. A single dose of up to 100 mg daily may be used. If 120 mg daily is required, the dose may be divided into 2 doses of 60 mg. The duration of treatment depends on clinical need.

Eradication of H. pylori: Patients with H. pylori should be treated with appropriate combinations of the drug with eradication therapy. It is recommended to administer for 7 days:

Rabimac 20 mg 2 times a day + clarithromycin 500 mg 2 times a day and amoxicillin 1 g 2 times a day.

For indications requiring only once-daily administration, the tablets should be taken in the morning before a meal. Although neither mid-day administration nor food intake has been shown to affect the action of rabeprazole sodium, this mode of administration is more favorable for treatment. The tablets should not be chewed or crushed, but should be swallowed whole.

Renal and hepatic impairment. Patients with renal or hepatic impairment do not require dose adjustment. For information on the use of the drug in patients with severe hepatic impairment, see the section "Special warnings and precautions for use".

Children

Rabimac is not recommended for use in children, as there is currently insufficient experience with its use in patients of this age group.

Overdose

Experience with intentional or accidental overdose is limited. The maximum dose studied did not exceed 60 mg rabeprazole sodium twice daily or 160 mg rabeprazole sodium once daily. Symptoms occurring in case of overdose are generally minimal, typical of the known adverse event profile and resolve without the need for further medical intervention.

There is no specific antidote for Rabimac. Rabeprazole sodium is highly bound to plasma proteins and is not removed by dialysis. In case of overdose, symptomatic and supportive therapy should be administered.

Adverse reactions

The most frequently reported adverse reactions were headache, diarrhea, abdominal pain, asthenia, flatulence, rash, and dry mouth. The adverse effects observed were mostly minor, moderate, and self-limiting.

The adverse reactions listed below have been reported during clinical trials and in the post-marketing period.

Frequency is defined as: common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (< 1/10000), unknown (cannot be estimated from the available data).

Infections and infestations: common – infections.

From the blood and lymphatic system: rarely - neutropenia, leukopenia, thrombocytopenia, leukocytosis.

Immune system disorders: Rare: hypersensitivity1,2

Metabolism and nutrition disorders: rare – anorexia; unknown – hypomagnesemia4, hyponatremia.

On the part of the psyche: often - insomnia; infrequently - nervousness; rarely - depression; unknown - confusion.

From the nervous system: often - headache, dizziness; infrequently - drowsiness.

On the part of the organs of vision: rarely - visual disturbances.

Vascular disorders: not known – peripheral edema.

On the part of the digestive tract: often - diarrhea, vomiting, nausea, abdominal pain, constipation, flatulence, benign fungicidal polyp; infrequently - dyspepsia, dry mouth, belching; rarely - gastritis, stomatitis, taste disturbance; unknown - microscopic colitis.

Hepatobiliary system: rarely – hepatitis, jaundice, hepatic encephalopathy3.

Skin and subcutaneous tissue disorders: uncommon - rash, erythema2; rare - pruritus, sweating, bullous reactions2; very rare - erythema multiforme, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome;

unknown – subacute cutaneous lupus erythematosus4.

Musculoskeletal system: often - non-specific pain, back pain; infrequently - myalgia, leg cramps, arthralgia, fracture of the femoral neck, wrist or spine4.

Renal and urinary disorders: uncommon – urinary tract infections; rare – interstitial nephritis.

From the reproductive system: unknown - gynecomastia.

General disorders: often - asthenia, flu-like syndrome; infrequently - chest pain, chills, pyrexia.

Laboratory tests: infrequently - increased liver enzymes3; rarely - increased body weight.

1 - Including facial edema, hypotension, and dyspnea.

2 - Erythema, bullous reactions and hypersensitivity reactions usually resolved after discontinuation of treatment.

3 - In isolated cases, hepatic encephalopathy has been observed in patients with cirrhosis.

Caution should be exercised when prescribing rabeprazole to patients with severe hepatic impairment (see section 4.4).

4 - See section "Application features".

Adverse reactions of clinical significance: shock and anaphylactic reactions; pancytopenia, leukopenia, agranulocytosis, hemolytic anemia; fulminant hepatitis, liver dysfunction, jaundice; interstitial pneumonia; toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme; acute renal failure, interstitial nephritis; hyponatremia; rhabdomyolysis.

Adverse reactions that are of clinical significance and are typical of proton pump inhibitors: visual disturbances, angioedema, bronchial spasm, confusion.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product has been authorised is important. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Expiration date

2 years.

Storage conditions

Store at a temperature not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging

15 tablets in a blister, 2 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

McLeods Pharmaceuticals Limited.

Location of the manufacturer and its business address

Village Theda, PO Lodhimaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.