Veloz

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VEL0Z (VELOZ)

Composition:

Active substance: rabeprazole;

1 tablet contains sodium rabeprazole 20 mg;

Excipients: magnesium oxide light, mannitol (E 421), crospovidone (XL-10), sodium hydroxide, povidone K-30, magnesium stearate, colloidal anhydrous silicon dioxide;

Coating composition (primer layer): hydroxypropylmethylcellulose, colloidal anhydrous silicon dioxide, ethylcellulose, talc, diethyl phthalate;

Coating composition (enteric coating): hypromellose phthalate, titanium dioxide (E 171), yellow iron oxide (E 172), talc, diethyl phthalate.

Pharmaceutical form. Enteric-coated tablets.

Main physicochemical properties: yellow, round, biconvex, film-coated tablets.

Pharmacotherapeutic group.

Agents for treatment of peptic ulcer and gastroesophageal reflux disease. Proton pump inhibitors. ATC code A02BC04.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Sodium rabeprazole belongs to the class of antisecretory compounds substituted benzimidazoles. It 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 plasma and gastric mucosa. Sodium rabeprazole has weakly basic properties, is rapidly absorbed at all doses, and accumulates in parietal cells. Sodium rabeprazole is converted into its active sulfenamide form via protonation and thereby reacts with accessible cysteine residues of the proton pump.

Antisecretory activity. After oral administration of 20 mg sodium rabeprazole, antisecretory effect is observed within 1 hour and reaches maximum within 2–4 hours. The inhibitory effect on basal acid output and food-stimulated acid secretion 23 hours after the first dose was 69% and 82%, respectively, with the duration of effect lasting up to 48 hours. The acid-suppressing efficacy of sodium rabeprazole slightly increases with daily administration of 1 tablet, but steady suppression of acid secretion is achieved within 3 days after initiation of treatment. After discontinuation of sodium rabeprazole, secretory activity returns to normal within 2–3 days.

Reduction of gastric acidity, regardless of the cause, 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. After administration of 10 or 20 mg sodium rabeprazole once daily for 3–4 months, serum gastrin concentration increases during the first 2–8 weeks of therapy, reflecting acid secretion inhibition. Gastrin concentrations typically return to baseline levels within 1–2 weeks after discontinuation of treatment.

Examination of biopsy samples from the gastric fundus and antrum in numerous patients treated with rabeprazole or a comparator drug for 8 weeks revealed no histological changes, no significant gastritis, no increased frequency of atrophic gastritis, intestinal metaplasia, or spread of H. pylori infection. During long-term treatment lasting 36 months, no significant changes were observed in these parameters.

Other effects. Currently, there are no data on systemic effects on the central nervous system (CNS), cardiovascular, or respiratory systems caused by sodium rabeprazole. Oral administration of 20 mg sodium rabeprazole daily for 2 weeks does not affect thyroid function, carbohydrate metabolism, or blood concentrations of parathyroid hormone, cortisol, estrogen, testosterone, prolactin, cholecystokinin, secretin, glucagon, follicle-stimulating hormone (FSH), luteinizing hormone (LH), renin, aldosterone, or growth hormone. Studies have shown no clinically significant interactions between rabeprazole and amoxicillin.

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

Pharmacokinetics

Absorption. Vezo – enteric-coated tablets. Absorption of sodium rabeprazole begins only after the tablet passes through the stomach. Sodium rabeprazole 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 within the dose range of 10–40 mg. Absolute bioavailability after oral administration of 20 mg (compared to intravenous administration) is approximately 52%, primarily due to first-pass metabolism. Additionally, bioavailability does not increase with repeated administration of sodium rabeprazole. The elimination half-life from plasma is approximately 1 hour (ranging from 0.7 to 1.5 hours), and total clearance is estimated at 283 ± 98 mL/min.

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

Metabolism and excretion. Like other members of the proton pump inhibitor class, rabeprazole is metabolized by the hepatic cytochrome P450 (CYP450) drug metabolism system. In vitro studies using human liver microsomes have shown that sodium rabeprazole is metabolized by CYP450 isoenzymes (CYP2C19 and CYP3A4). At expected plasma concentrations in humans, rabeprazole neither induces nor inhibits CYP3A4. However, as in vitro findings cannot always be extrapolated to in vivo situations, these results suggest that interaction between rabeprazole and cyclosporine is not expected. In humans, the main metabolites present in plasma are the thioether (M1) and the carboxylic acid (M6). Minor metabolites present at low concentrations include the sulfone (M2), dimethylthioether (M4), and the 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, unchanged rabeprazole was not detected in urine. Approximately 90% of the administered dose was eliminated in urine, primarily as two metabolites: the mercapturic acid conjugate (M5) and the carboxylic acid (M6), along with two unidentified metabolites. The remaining portion of the dose was recovered in feces.

Gender differences. Since the single 20 mg dose of sodium rabeprazole is adjusted for body weight and height, gender differences do not affect pharmacokinetic parameters.

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 were approximately 35% higher in these patients 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 hemodialysis 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 the elimination half-life was increased 2–3 times compared to healthy volunteers. Thus, with daily administration of 20 mg for 7 days, AUC is expected to increase by at least 1.5 times, while changes in peak plasma concentrations (Cmax) are up to 1.2 times. The elimination half-life in patients with liver disease was 12.3 hours compared to 2.1 hours in healthy volunteers. Pharmacodynamic response (intragastric pH-metry) was similar between the two patient groups in terms of therapeutic parameters.

Elderly patients. Elimination of sodium rabeprazole is somewhat reduced in elderly patients. After 7 days of 20 mg daily sodium rabeprazole administration, AUC was approximately twice as high, Cmax increased by 60%, and T½ increased by 30% compared to young healthy volunteers. However, there was no evidence of sodium rabeprazole accumulation.

CYP2C19 polymorphism. After 7 days of 20 mg daily sodium rabeprazole administration in patients with slow CYP2C19 metabolism, AUC and elimination half-life were approximately 1.9 and 1.6 times higher, respectively, compared to patients with rapid metabolism, while Cmax increased only by 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 treatment regimens for eradication of Helicobacter pylori (H. pylori) in patients with gastric and duodenal peptic ulcers.

Contraindications.

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

Pregnancy or breastfeeding period.

Interaction with other medicinal products and other forms of interaction.

CYP450 system

Sodium rabeprazole is metabolized by the hepatic CYP450 enzyme system, 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 due to inhibition of gastric acid secretion

Sodium rabeprazole causes strong and prolonged reduction in gastric acid production. Therefore, rabeprazole may interact with drugs whose absorption depends on the pH of gastric contents. Concomitant administration of sodium rabeprazole with ketoconazole or itraconazole may lead to reduced plasma concentrations of the latter, while administration with digoxin may lead to increased digoxin concentrations. Thus, individual patients receiving these drugs concomitantly with Veloze should be monitored by a physician to determine whether dose adjustment is necessary.

Antacids

During clinical trials, patients received antacids as needed concomitantly with Veloze; in a specific study, no interaction between the drug and liquid forms of antacids was observed.

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, should not be used in combination with atazanavir.

Methotrexate

Case reports, published data from population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of methotrexate and proton pump inhibitors (especially 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 did not have a clinically significant effect on concentrations of the active metabolite of clopidogrel. Dose adjustment is not required.

Food

Studies have shown that consumption 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 cyclosporine metabolism. This level of inhibition is comparable to that of omeprazole.

Medicinal products not recommended for concomitant use with rabeprazole

Medicinal products that should be prescribed with caution

Special precautions for use.

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

Use in elderly patients

Rabeprazole 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 closely and dosing recommendations and treatment duration guidelines should be strictly followed.

Symptomatic improvement with rabeprazole therapy does not exclude the presence of a malignant tumor of the stomach or esophagus; therefore, the presence of malignancy should be ruled out before initiating rabeprazole therapy.

Patients undergoing long-term treatment (particularly those treated for more than 1 year) should be monitored regularly.

The risk of developing cross-hypersensitivity reactions when used with other proton pump inhibitors or substituted benzimidazoles is not excluded.

Patients should be informed that Vezo tablets must not be chewed or crushed but should be swallowed whole.

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

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

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; abnormalities were uncomplicated and resolved after discontinuation of rabeprazole.

During studies, no significant difference in the frequency of adverse effects was observed between patients with mild or moderate hepatic impairment and the control group of corresponding sex and age receiving rabeprazole. Physicians should exercise caution when prescribing rabeprazole during the initial 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.

During rabeprazole therapy, periodic hematological and biochemical testing is recommended.

Concomitant use of atazanavir and rabeprazole is not recommended.

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

Fracture risk

Proton pump inhibitors, 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 in patients with other existing risk factors. Observational studies suggest that proton pump inhibitors may increase the overall risk of fractures by 10–40%. The 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 proton pump inhibitors for at least 3 months, and in most cases, for a year or longer. Serious manifestations of hypomagnesemia may occur, such as weakness, tetany, delirium, seizures, dizziness, and ventricular arrhythmia. In most patients, hypomagnesemia resolved after discontinuation of proton pump inhibitors and replacement therapy with magnesium supplements.

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

Thyroid function

During animal studies, an increase in thyroid gland weight and elevated serum thyroxine levels were observed. Monitoring of thyroid function is recommended during rabeprazole therapy.

Renal function

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

If TIN is suspected, rabeprazole should be discontinued immediately and appropriate treatment initiated without delay.

Special considerations for breath tests

Results of C-urea breath tests may be falsely negative during treatment with proton pump inhibitors such as rabeprazole, and antibiotics such as amoxicillin, clarithromycin, and metronidazole. Therefore, breath tests to detect Helicobacter pylori should not be performed earlier than 4 weeks after discontinuation of these medications.

Treatment of non-erosive reflux disease is indicated in patients with recurrent reflux symptoms, particularly heartburn and acid regurgitation (approximately twice a week). Rabeprazole therapy may mask symptoms of malignancy (e.g., gastric or intestinal cancer) and other gastrointestinal disorders. Therefore, such conditions should be excluded before initiating rabeprazole therapy.

When rabeprazole is prescribed for patients with erosive reflux disease, the physician should assess treatment efficacy after 2 weeks of therapy. If symptoms persist, it is likely that reflux disease is not the cause. In such cases, the physician should consider alternative treatment approaches.

If rabeprazole is prescribed for Helicobacter pylori eradication, it is important to consider the contraindications, special precautions, clinically significant adverse reactions, and other warnings stated in the medical instructions for other medicinal products used for eradication.

Literature data suggest that concomitant use of proton pump inhibitors and methotrexate (particularly at high doses) may increase methotrexate and/or its metabolite levels in blood plasma, potentially leading to methotrexate-related toxicity. When high-dose methotrexate is required, discontinuation of proton pump inhibitor therapy should be considered.

Use during pregnancy or breastfeeding.

Pregnancy

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

Use of Vezo during pregnancy is contraindicated.

Breastfeeding

It is unknown whether sodium rabeprazole passes into breast milk. Appropriate studies have not been conducted.

Vezo should not be administered to women who are breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Considering the pharmacodynamics of sodium rabeprazole and its known adverse effect profile, Vezo is not expected to negatively affect the ability to drive or operate machinery. However, if drowsiness occurs, driving or operating machinery should be avoided.

Method of Administration and Dosage

Adults, including elderly patients.

Active duodenal 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 ulcer, healing occurs within 4 weeks. However, some patients may require additional treatment with Veloz for another 4 weeks to achieve healing. In most patients with active benign gastric ulcer, healing occurs within 6 weeks, but some treatment-resistant patients may require additional therapy with Veloz for up to 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 management, maintenance doses of rabeprazole 10 mg or 20 mg once daily may be used (depending on treatment efficacy).

Symptomatic treatment of mild to very severe GERD: Patients without esophagitis should be treated with rabeprazole 10 mg once daily. If symptoms persist after 4 weeks of treatment, further patient evaluation is recommended. Once symptoms resolve, symptom control can be maintained using an "on-demand" regimen: 10 mg once daily as needed.

Zollinger-Ellison syndrome: The dose should be individually adjusted.

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.

Some patients with Zollinger-Ellison syndrome have been treated with sodium rabeprazole for up to 1 year.

Eradication of H. pylori: Patients with H. pylori infection should receive appropriate combinations of Veloz with antibiotics. A 7-day regimen is recommended:

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

For indications requiring once-daily administration, Veloz tablets should be taken in the morning before a meal. Although administration in the morning or food intake has not been shown to affect the action of sodium rabeprazole, this regimen is considered more favorable for treatment. Veloz tablets must not be chewed or crushed; they should be swallowed whole.

Renal and hepatic impairment. Dose adjustment is not required in patients with renal or hepatic impairment. For information on use in patients with severe hepatic impairment, see section "Special precautions for use."

Children

Veloz 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. No symptoms related to overdose have been reported. The maximum studied dose did not exceed 180 mg of sodium rabeprazole once daily during treatment of Zollinger-Ellison syndrome.

There is no known specific antidote for Veloz. Sodium rabeprazole is highly protein-bound and is not dialyzable. In case of overdose, symptomatic and supportive therapy 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 mostly mild, moderate, and transient.

Infections and infestations: infections.

Blood and lymphatic system disorders: anemia, eosinophilia, erythrocytopenia, lymphopenia, neutropenia, leukopenia, thrombocytopenia, leukocytosis.

Immune system disorders: hypersensitivity (including urticaria, facial swelling, arterial hypotension, and dyspnea; erythema, bullous reactions, and acute systemic allergic reactions, which usually resolve after discontinuation of treatment).

Metabolism and nutrition disorders: anorexia, hypomagnesemia, hyponatremia.

Psychiatric disorders: insomnia, nervousness, depression, confusion.

Nervous system disorders: headache, dizziness, somnolence, weakness in limbs, limb numbness, paresthesia, decreased grip strength, speech disorder, disorientation, delirium, coma.

Eye disorders: visual disturbances, increased intraocular pressure.

Cardiac disorders: peripheral edema, arterial hypertension, palpitations.

Respiratory, thoracic and mediastinal disorders: cough, pharyngitis, rhinitis, bronchitis, sinusitis, glossitis.

Gastrointestinal disorders: diarrhea, vomiting, nausea, abdominal pain, constipation, flatulence, bloating and heaviness in the stomach, candidiasis, dyspepsia, dry mouth, belching, gastritis, stomatitis, taste disturbance, enteritis, esophagitis, cheilitis, heartburn, hemorrhoids.

Hepatobiliary disorders: hepatitis, jaundice, hepatic encephalopathy¹.

Skin and subcutaneous tissue disorders: rash, erythema (bullous reactions and hypersensitivity reactions, which usually resolve after discontinuation of treatment), pruritus, increased sweating, bullous reactions, erythema multiforme, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders: non-specific pain, back pain, myalgia, leg cramps, arthralgia, fracture of the femoral neck, wrist, or spine.

Renal and urinary disorders: urinary tract infections, tubulointerstitial nephritis (with possible progression to renal failure).

Reproductive system and breast disorders: gynecomastia, prolonged erection.

General disorders and administration site conditions: asthenia, influenza-like syndrome, malaise, chest pain, chills, pyrexia, thirst, alopecia.

Investigations: increased levels of liver enzymes (ALT, AST), LDH, gamma-glutamyltransferase, alkaline phosphatase, total bilirubin; weight gain; proteinuria; increased levels of total cholesterol, triglycerides, blood urea nitrogen; elevated TSH, CK, uric acid, glucose in urine; hyperammonemia.

¹In isolated cases, hepatic encephalopathy was observed in patients with cirrhosis.

Caution should be exercised when prescribing rabeprazole to patients with severe hepatic impairment.

Clinically significant adverse reactions: shock and anaphylactic reactions; pancytopenia, leukopenia, agranulocytosis, hemolytic anemia; fulminant hepatitis, hepatic dysfunction, 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.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets per strip, 2 or 3 strips per cardboard package.

Prescription status. Prescription only.

Manufacturer.

Torrent Pharmaceuticals Ltd.

Manufacturer's address and site of operation.

Indrad Plant, Vill. Indrad, Taluka Kadi, Dist. Mehsana, Gujarat 382721, India