Rabigem 20

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Rabigem 20 (Rabigem 20)

Composition:

Active substance: rabeprozole sodium;

1 tablet contains 20 mg of rabeprozole sodium;

Excipients: magnesium oxide light, mannitol (E 421), hydroxypropylcellulose, crospovidone, purified talc, magnesium stearate, EN-HPMCP brown coating (A34D00076) (iron oxide red (E 172) and titanium dioxide (E 171)).

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties: pink, round, biconvex tablets with an enteric coating, smooth on both sides.

Pharmacotherapeutic group.

Drugs affecting the digestive tract and metabolism. Drugs for the treatment of diseases associated with acid imbalance. Anti-ulcer drugs and drugs for the treatment of gastroesophageal reflux. Proton pump inhibitors. Rabeprozole.

ATC code A02B C04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Sodium rabeprazole belongs to the class of antisecretory compounds substituted benzimidazoles, has no anticholinergic properties and is not a histamine H2-receptor antagonist, but inhibits gastric acid secretion by specifically inhibiting the H+/K+-ATPase enzyme at the secretory surface of gastric parietal cells (the acid or proton pump). The effect is dose-dependent and results in inhibition of both basal and stimulated acid secretion regardless of the stimulus. Animal studies have shown that after administration, sodium rabeprazole rapidly disappears from both blood plasma and gastric mucosa. Sodium rabepr inflamm has weakly basic properties, is rapidly absorbed at all dosage levels, and accumulates in parietal cells. Sodium rabeprazole is converted to its active sulfonamide form via protonation and thereby reacts with accessible cysteine residues of the proton pump.

Antisecretory activity. After oral administration of 20 mg of sodium rabeprazole, the antisecretory effect is observed within 1 hour and reaches maximum within 2–4 hours. Inhibition of basal acid secretion and food-stimulated acid secretion 23 hours after the first dose of sodium rabeprazole was 69% and 82%, respectively, and the duration of inhibition lasted up to 48 hours. The inhibitory effect of sodium rabeprazole is slightly enhanced after repeated once-daily administration, with stable inhibition of secretion achieved by day 3. After discontinuation of sodium rabeprazole, secretory activity returns to normal within 2–3 days.

Reduction of gastric 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 concentration. In clinical trials, patients received 10 or 20 mg of sodium rabeprazole once daily for up to 43 months. During the first 2–8 weeks of therapy, serum gastrin concentration increased, reflecting inhibition of acid secretion. Gastrin concentrations generally returned to baseline levels within 1–2 weeks after discontinuation of treatment.

Examination of biopsy samples from the gastric fundus and antrum in over 500 patients who received rabeprazole or a comparator drug for 8 weeks revealed no histological changes in ECL cells, degree of gastritis, increased frequency of atrophic gastritis, intestinal metaplasia, or spread of H. pylori infection. In long-term treatment studies involving over 250 patients for 36 months, no significant changes were observed in the results of these analyses.

Other effects. Currently, there is no information on systemic effects on the central nervous system (CNS), cardiovascular, or respiratory systems caused by the administration of sodium rabeprazole. Oral administration of 20 mg of sodium rabeprazole daily for 2 weeks did not affect thyroid function, carbohydrate metabolism, or plasma concentrations of parathyroid hormone, cortisol, estrogen, testosterone, prolactin, cholecystokinin, secretin, glucagon, follicle-stimulating hormone (FSH), luteinizing hormone (LH), renin, aldosterone, or growth hormone.

Studies in healthy volunteers showed no clinically significant interactions between rabeprazole and amoxicillin. Rabeprazole has no negative effect on plasma levels of amoxicillin and clarithromycin when administered concomitantly for the eradication of H. pylori infection in the upper gastrointestinal tract.

During treatment with antisecretory drugs, serum gastrin levels increase in response to reduced acid secretion. Also, due to decreased gastric acidity, plasma levels of chromogranin A increase. Elevated chromogranin A levels may affect test results for detecting neuroendocrine tumors.

Available published data indicate that proton pump inhibitors should be discontinued 5 days to two weeks before measuring chromogranin A levels to allow levels to return to reference values if elevated during treatment with proton pump inhibitors.

Pharmacokinetics.

Absorption. Rabijem 20 is a drug product containing sodium rabeprazole as the active ingredient, formulated as enteric-coated tablets. This dosage form is necessary because sodium rabeprazole is susceptible to degradation by gastric acid. Absorption of sodium rabeprazole begins only after the tablet passes through the stomach. Sodium rabeprazole is rapidly absorbed from the intestine. Peak plasma concentration (Cmax) of rabeprazole is reached approximately 3.5 hours after administration of a 20 mg dose. The plasma Cmax and AUC of rabeprazole show a linear relationship within the dose range of 10 to 40 mg. Absolute bioavailability after oral administration of 20 mg (compared to intravenous administration) is approximately 52%, primarily due to first-pass metabolism. Furthermore, bioavailability does not increase with repeated administration of sodium rabeprazole. In healthy volunteers, the plasma half-life was approximately 1 hour (ranging from 0.7 to 1.5 hours), and total clearance was estimated at 283±98 mL/min. No clinically significant interaction with food was observed. Neither food type nor time of day of administration affects the absorption of sodium rabeprazole.

Distribution. In humans, the plasma protein binding of sodium rabeprazole is approximately 97%.

Metabolism and excretion. Like other proton pump inhibitors, rabeprazole is metabolized by the hepatic cytochrome P450 (CYP450) drug metabolism system. In vitro studies with human liver microsomes have shown that sodium rabeprazole is metabolized by CYP450 isoenzymes (CYP2C19 and CYP3A4). At expected human plasma concentrations, rabeprazole does not induce or inhibit CYP3A4. However, in vitro studies cannot always be extrapolated to in vivo situations; these results suggest that interactions between rabeprazole and cyclosporine are not expected. In humans, the main metabolites present in plasma are thioether (M1) and carboxylic acid (M6), while minor metabolites present at low concentrations include sulfone (M2), dimethylthioether (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 20 mg dose of 14C-labeled sodium rabeprazole, no unchanged rabeprazole was detected in urine. Approximately 90% of the administered dose was eliminated in urine, primarily as two metabolites: mercapturic acid conjugate (M5) and carboxylic acid (M6), along with two unknown metabolites. The remainder of the dose was recovered in feces.

Gender. After correction for body weight and height, there are no significant differences in the pharmacokinetics of rabeprazole related to gender.

Renal impairment. In patients with end-stage chronic renal failure undergoing maintenance hemodialysis (creatinine clearance ≤5 mL/min/1.73 m²), the disposition of sodium rabeprazole was very similar to that in healthy volunteers. AUC and Cmax of sodium rabeprazole in these patients were approximately 35% lower compared to healthy volunteers. The mean elimination half-life was 0.82 hours in healthy volunteers, 0.95 hours in hemodialysis patients, and 3.6 hours in post-dialysis patients. Drug clearance in dialysis patients with renal impairment was approximately twice that in healthy volunteers.

Hepatic impairment. After a single 20 mg dose of sodium rabeprazole in patients with moderate chronic liver disease, AUC was doubled and a 2–3-fold increase in elimination half-life of rabeprazole was observed compared to healthy volunteers. Although after 7 days of daily administration of 20 mg, AUC increased only 1.5-fold and Cmax increased 1.2-fold. The elimination half-life in patients with impaired liver function was 12.3 hours compared to 2.1 hours in healthy volunteers. Pharmacodynamic response (gastric juice pH-metry) was comparable between the two patient groups.

Elderly patients. In elderly patients, elimination of sodium rabeprazole is somewhat reduced. After 7 days of treatment with 20 mg sodium rabeprazole daily, AUC was approximately twice as high, Cmax increased by 60%, and t1/2 increased by 30% compared to young healthy volunteers. However, it should be noted that there were no signs of accumulation of sodium rabeprazole.

CYP2C19 polymorphism. After 7 days of treatment with 20 mg sodium rabeprazole daily, patients with slow CYP2C19 metabolism had AUC (area under the curve) and t1/2 (elimination half-life) values approximately 1.9 and 1.6 times higher, respectively, compared to patients with rapid metabolism; meanwhile, Cmax increased by only 40%.

Clinical characteristics.

Indications.

• Active duodenal peptic ulcer;

• active benign gastric ulcer;

• erosive or ulcerative gastroesophageal reflux disease (GERD);

• long-term treatment of gastroesophageal reflux disease (maintenance therapy for GERD);

• symptomatic treatment of moderate to very severe gastroesophageal reflux disease (symptomatic treatment of GERD);

• Zollinger–Ellison syndrome;

• in combination with appropriate antibacterial therapeutic regimens for eradication of Helicobacter pylori (H. pylori) in patients with gastric and duodenal peptic ulcers.

Contraindications.

Hypersensitivity to rabeprazole or to any of the excipients of the medicinal product.

Pregnancy and breastfeeding period (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

CYP450 system

Sodium rabeprazole is metabolized by the hepatic enzyme system CYP450, specifically CYP2C19 and CYP3A4.

Studies have shown that sodium rabeprazole 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

Sodium rabeprazole causes strong and prolonged inhibition of gastric acid secretion. Therefore, rabeprazole may interact with drugs whose absorption depends on the pH of gastric contents. Concomitant administration of sodium rabeprazole and ketoconazole or itraconazole may lead to reduced plasma concentrations of the latter. Therefore, patients receiving these drugs together with the medicinal product Rabijem 20 should be under medical supervision to determine the need for dose adjustment.

Antacids

During clinical trials, patients took antacids as needed concomitantly with the medicinal product Rabijem 20; no interaction with antacids was observed in a dedicated study.

Atazanavir

Concomitant 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 reduction in atazanavir exposure. Atazanavir absorption is pH-dependent. Although no studies have been conducted, similar results are expected with other proton pump inhibitors. Proton pump inhibitors, including rabeprazole, are contraindicated for use in combination with atazanavir (see section "Special precautions for use").

Metotrexate

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

Clopidogrel

Concomitant administration of clopidogrel and rabeprazole to healthy volunteers had no clinically significant effect on concentrations of the active metabolite of clopidogrel. Dose adjustment is not required.

Food

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

Cyclosporine

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

Medicinal products contraindicated for concomitant use with rabeprazole

Medicinal products that should be prescribed with caution

Special precautions for use.

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

Use in elderly patients

Rabijem 20 is metabolized exclusively in the liver. Since hepatic physiological function may decline with age, adverse reactions may occur in elderly patients. Therefore, elderly patients should be monitored and dosing recommendations and treatment duration guidelines should be strictly followed.

Symptomatic improvement in response to rabeprozole therapy does not exclude the presence of a malignant tumor of the stomach or esophagus; therefore, malignancy must be ruled out before initiating treatment with Rabijem 20.

Patients undergoing long-term treatment (especially those treated for more than one year) should be regularly monitored.

The risk of developing cross-sensitivity reactions to other proton pump inhibitors or substituted benzimidazoles cannot be excluded.

Patients should be advised that Rabijem 20 tablets must not be chewed or crushed, but swallowed whole.

Rabijem 20 is not recommended for use in children, as there is no experience with use in this patient population.

During the post-marketing period, pathological blood changes (thrombocytopenia and neutropenia) have been reported. In most cases, no other etiology was identified; the cases were uncomplicated and resolved after discontinuation of rabeprozole.

Abnormalities in liver enzymes have been observed both during clinical trials and in the post-marketing period. In most cases, no other etiology was identified; the cases were uncomplicated and resolved after discontinuation of rabeprozole.

In patients with mild to moderate hepatic impairment, no significant differences in the frequency of adverse effects were observed during administration of Rabijem 20 tablets compared to the control group of corresponding sex and age who did not receive the drug.

Physicians should exercise caution when prescribing Rabijem 20 at the early stages of therapy to patients with severe hepatic impairment, as there are no clinical data on the use of the drug in this patient group.

Concomitant use of atazanavir and Rabijem 20 is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Treatment with proton pump inhibitors (PPIs), including rabeprozole, increases the risk of gastrointestinal infections caused by Salmonella, Campylobacter, and Clostridium difficile (see section "Pharmacodynamics").

Fracture risk

PPIs, particularly when used at high doses and for prolonged periods (more than 1 year), may increase the risk of fractures of the hip, wrist, and spine, primarily in elderly patients or patients with other existing risk factors. Observational studies suggest that PPIs may increase the overall risk of fractures by 10–40%. Risk may also be elevated due to other factors. Patients at risk of osteoporosis should receive appropriate treatment and take vitamin D and calcium supplements.

Hypomagnesemia

Cases of severe hypomagnesemia have been reported in patients taking PPIs for at least 3 months, and in most cases, for one year or longer. Serious manifestations of hypomagnesemia such as weakness, tetany, delirium, seizures, dizziness, and ventricular arrhythmia may occur unexpectedly and may go undetected. In most patients, hypomagnesemia resolved after discontinuation of PPI and magnesium replacement therapy.

During long-term treatment or concomitant use of PPIs with digoxin or other drugs that may lead to hypomagnesemia (e.g., diuretics), physicians should monitor serum magnesium levels before treatment initiation and periodically during treatment.

Concomitant use of rabeprozole with methotrexate

Published data suggest that concomitant use of PPIs and methotrexate (particularly at high doses) may increase methotrexate and/or its metabolite levels in blood serum, potentially leading to methotrexate-related toxicity. If high-dose methotrexate is required, discontinuation of PPI therapy should be considered.

Effect on vitamin B12 absorption

Sodium rabeprozole, like all drugs that suppress gastric acid secretion, may reduce absorption of vitamin B12 (cyanocobalamin) due to hypo- or achlorhydria. This should be considered in cases of low body weight or presence of risk factors for reduced vitamin B12 absorption during long-term treatment or when relevant clinical symptoms are present.

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 develop, especially in sun-exposed areas, accompanied by arthralgia, patients should seek immediate medical attention, and physicians should consider discontinuing treatment with Rabijem 20. Previous treatment with a proton pump inhibitor may increase the risk of developing subacute cutaneous lupus erythematosus when other PPIs are used.

Renal function impairment

Acute tubulointerstitial nephritis (ATIN) has been observed in patients taking rabeprozole and may occur at any time during rabeprozole therapy (see section "Adverse reactions"). Acute tubulointerstitial nephritis may progress to renal failure.

If ATIN is suspected, rabeprozole should be discontinued immediately and appropriate treatment initiated without delay.

Effect on laboratory test results

Elevated chromogranin A (CgA) levels may interfere with testing for neuroendocrine tumors. To avoid false results, treatment with rabeprozole should be discontinued at least 5 days before measuring CgA (see section "Pharmacokinetics"). If CgA and gastrin levels have not returned to reference ranges after initial testing, the test should be repeated 14 days after discontinuation of PPI.

The product contains mannitol (E 421), which may exert a mild laxative effect.

Use during pregnancy or breastfeeding

Pregnancy

There are no data on the safety of rabeprozole use during pregnancy.

Reproductive toxicity studies in rats and rabbits did not show evidence of impaired fertility or fetal harm associated with sodium rabeprozole administration; however, slight placental transfer was observed in rats. The use of Rabijem 20 during pregnancy is contraindicated.

Breastfeeding

It is unknown whether sodium rabeprozole passes into human breast milk. Adequate studies in breastfeeding women have not been conducted.

Sodium rabeprozole passes into the milk of rats. Rabijem 20 should not be administered to women during breastfeeding.

Ability to affect reaction speed when driving or operating machinery

Considering the pharmacodynamic properties of sodium rabeprozole and its known side effect profile, Rabijem 20 is not expected to negatively affect the ability to drive a car or operate potentially hazardous machinery. However, if drowsiness occurs, patients are advised to avoid driving and operating machinery.

Dosage and Administration.

Adults and elderly patients.

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

For most patients with active duodenal ulcer, healing occurs within 4 weeks. However, some patients may require additional treatment with Rabijem 20 for another 4 weeks to achieve healing. In most patients with active benign gastric ulcer, healing occurs within 6 weeks, but some patients who are less responsive to treatment may require additional therapy with Rabijem 20 for another 6 weeks.

Erosive or ulcerative gastroesophageal reflux disease (GERD): the recommended dose for these conditions is 20 mg once daily for 4–8 weeks.

Long-term treatment of gastroesophageal reflux disease (maintenance therapy for GERD): for long-term use, maintenance doses of Rabijem 20 at 10 mg* or 20 mg once daily may be used (depending on the patient's clinical response).

Symptomatic treatment of mild to very severe GERD: patients without esophagitis should be treated with Rabijem 20 at a dose of 10 mg once daily. If symptoms do not resolve after 4 weeks of treatment, further patient evaluation is recommended. Once symptoms have resolved, ongoing symptom control can be achieved using an "on-demand" regimen: take 10 mg once daily as needed.

Zollinger-Ellison syndrome: the recommended initial dose is 60 mg once daily. The dose may be gradually increased up to 120 mg daily if clinically necessary. A single daily dose of up to 100 mg may be used. If a daily dose of 120 mg is required, the dose should be divided into two administrations of 60 mg each. The duration of treatment depends on clinical necessity.

H. pylori eradication: for patients with H. pylori, the drug should be used in combination with eradication therapy. A 7-day regimen is recommended:

• Rabijem 20–20 mg twice daily + clarithromycin 500 mg twice daily and amoxicillin 1 g twice daily.

For indications requiring once-daily dosing, Rabijem 20 tablets should be taken in the morning before meals. Although administration during the first half of the day or food intake has not shown to affect the action of rabeprazole, this regimen is considered more favorable for treatment.

Renal and hepatic impairment. Patients with renal or hepatic impairment do not require dose adjustment of Rabijem 20. For information on use in patients with severe hepatic impairment, see section "Special precautions".

Administration method.

Patients should be instructed that Rabijem 20 tablets must not be chewed or crushed and should be swallowed whole.

* Use the drug in another pharmaceutical form allowing appropriate dosing.

Children.

Rabijem 20 is not recommended for use in children, as there is currently insufficient experience with its use in this age group.

Overdose.

Experience with intentional or accidental overdose is limited. The highest documented exposure did not exceed 60 mg of sodium rabeprazole twice daily or 160 mg once daily. Overall, effects were minimal, consistent with known adverse reactions, and reversible without further medical intervention. There is no known specific antidote for Rabijem 20. Sodium rabeprazole is highly protein-bound and is not dialyzable. In case of overdose, symptomatic and supportive treatment should be administered.

Adverse Reactions

The most commonly reported adverse reactions were headache, diarrhea, abdominal pain, asthenia, flatulence, rash, and dry mouth. The observed adverse effects were generally mild, moderate, and transient.

The adverse reactions listed below were 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), not known (cannot be estimated from available data).

Infections and infestations: common – infections.

Blood and lymphatic system disorders: rare – neutropenia, leukopenia, thrombocytopenia, leukocytosis.

Immune system disorders: rare – hypersensitivity^1,2.

Metabolism and nutrition disorders: rare – anorexia; not known – hyponatremia, hypomagnesemia⁴.

Psychiatric disorders: common – insomnia; uncommon – restlessness; rare – depression; not known – confusion.

Nervous system disorders: common – headache, dizziness; uncommon – somnolence.

Eye disorders: rare – visual disturbances.

Vascular disorders: not known – peripheral edema.

Respiratory system disorders: common – cough, pharyngitis, rhinitis; uncommon – bronchitis, sinusitis.

Gastrointestinal disorders: common – diarrhea, vomiting, nausea, abdominal pain, constipation, flatulence, benign fundic gland polyp; uncommon – dyspepsia, dry mouth, eructation; rare – gastritis, stomatitis, taste disturbance; not known – microscopic colitis.

Hepatobiliary disorders: rare – 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; not known – subacute cutaneous lupus erythematosus⁴.

Musculoskeletal and connective tissue disorders: common – nonspecific pain, back pain; uncommon – myalgia, leg cramps, arthralgia, fracture of the femoral neck, wrist or spine⁴.

Renal and urinary disorders: uncommon – urinary tract infections; rare – tubulointerstitial nephritis (with possible progression to renal failure).

Reproductive system and breast disorders: not known – gynecomastia.

General disorders and administration site conditions: common – asthenia, influenza-like illness; uncommon – chest pain, chills, pyrexia.

Investigations: uncommon – increased liver enzymes³; rare – weight increase.

¹ Including facial swelling, hypotension, and dyspnea.

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

³ Hepatic encephalopathy has been observed in isolated cases in patients with liver cirrhosis. Caution should be exercised when prescribing Rabij 20 to patients with severe hepatic impairment (see section "Special Warnings and Precautions for Use").

⁴ See section "Special Warnings and Precautions for Use".

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

Clinically significant adverse reactions associated with proton pump inhibitors: visual disturbances, angioneurotic edema, bronchospasm, confusion.

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging, protected from light, in a place inaccessible to children, at a temperature not exceeding 25 °C.

Packaging.

Enteric-coated tablets, 20 mg, 10 tablets per blister, 1 blister per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Tulip Lab Pvt. Ltd. /
Tulip Lab Pvt. Ltd.

Manufacturer's address and place of business.

F-20/21, Ranjangaon MIDC, Tal. Shirur, Dist. Pune, India /
F-20/21, Ranjangaon MIDC, Tal. Shirur, Dist. Pune, India.