Raso, 10 mg 15 pcs

Pharmacokinetics

Eabsorption

Rabeprazole is rapidly absorbed from the gut. After taking a dose of 20 mg, the Cmax of rabeprazole in plasma is reached after about 3.5 hours. Changes in Cmax and AUC are linear in the dose range from 10 to 40 mg. Absolute bioavailability after oral administration of 20 mg (compared with intravenous administration) is about 52% largely due to metabolism during “first passage” through the liver. In addition, bioavailability does not change with repeated administration of rabeprazole. Food intake and time of taking the drug during a day have no effect on absorption of rabeprazole.

Distribution

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

Metabolism

. The major metabolites present in plasma in humans are thioether (M1) and carboxylic acid (M6), and the minor metabolites present in low concentrations are sulfone (M2), demethylthioether (M4), and mercapturic acid conjugate (M5). Only the dimethyl metabolite (M3) has minor antisecretory activity, but it is not detected in plasma.

Evacuation

In healthy volunteers, the T1/2 is approximately 1 h (0.7-1.5 h) and total clearance is 283 ± 98 ml/min.

About 90% is excreted in the urine mainly as two metabolites: M5 and M6, about 10% is excreted in the feces.

Pharmacokinetics

in special clinical cases

In patients with stable terminal renal failure requiring maintenance hemodialysis (CK≤5 mL/min/1.73 m2) the distribution of rabeprazole was very close to that of healthy volunteers. AUC and Cmax in these patients were approximately 35% lower than in healthy volunteers. The average T1/2 of rabeprazole was 0.82 h in healthy volunteers, 0.95 h in patients during hemodialysis and 3.6 h after hemodialysis. Clearance of the drug in patients with kidney disease requiring hemodialysis was approximately 2 times higher than in healthy volunteers.

After a single dose of rabeprazole 20 mg in patients with chronic hepatic failure AUC was increased 2-fold and T1/2 was increased 2-3-fold compared to healthy volunteers. However, after taking rabeprazole at a dose of 20 mg/day for 7 days, AUC increased only 1.5 times, and Cmax – 1.2 times. T1/2 in patients with hepatic impairment was 12.3 h, compared with 2.1 h in healthy volunteers. Pharmacodynamic response (gastric pH control) was clinically comparable in both groups.

In elderly patients the excretion of rabeprazole is slightly delayed. In 7 days after taking rabeprazole sodium 20 mg/day in this category of patients the AUC was about 2 times higher and Cmax was 60% higher compared to young healthy volunteers. However, there were no signs of cumulation of rabeprazole.

In the case of delayed CYP2C19 metabolism, after taking rabeprazole at 20 mg/day for 7 days, AUC was 1.9 times higher and T1/2 was 1.6 times higher compared to the same parameters in “fast” metabolizers, while Cmax was increased by 40%.

Pharmacodynamics

Rabeprazole sodium belongs to the class of antisecretory compounds, which are chemically substituted benzimidazoles. Rabeprazole inhibits the activity of the enzyme H+-K+-ATPase, thus blocking the final stage of hydrochloric acid synthesis. This effect is dose-dependent and leads to inhibition of both basal and stimulated acid secretion regardless of the stimulant. As a weak base, rabeprazole at any dose is rapidly absorbed and concentrated in the acidic environment of the parietal cells.

Antisecretory activity. After oral administration of rabeprazole at a dose of 20 mg, the antisecretory effect occurs within 1 h and reaches a maximum after 2 – 4 h. Inhibition of basal and food stimulated acid secretion 23 h after the first dose of rabeprazole sodium was 62 and 82%, respectively, and the duration of this action reached 48 h.

The inhibitory effect of rabeprazole sodium on acid secretion increases slightly during daily administration of 1 tablet, stable inhibition of secretion is achieved 3 days after the start of the drug. After termination of rabeprazole administration, secretory activity is restored in 2-3 days.

Indications

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

Pharmacological effect

Pharmacotherapeutic group

A drug that reduces the secretion of gastric glands – a proton pump inhibitor.

ATX code: A02BC04

Pharmacological properties

Pharmacodynamics

Mechanism of action

Rabeprazole belongs to the class of antisecretory agents, which are chemically substituted benzimidazoles. Rabeprazole inhibits the activity of the enzyme H+/K+ATPase (“proton pump”), thereby blocking the final stage of hydrochloric acid synthesis. This effect is dose-dependent and leads to inhibition of both basal and stimulated secretion of hydrochloric acid, regardless of the stimulus.

Rabeprazole does not have anticholinergic properties.

Antisecretory activity

After oral administration of 20 mg of rabeprazole, the antisecretory effect occurs within an hour. The inhibition of basal and stimulated secretion of hydrochloric acid 23 hours after taking the first dose of rabeprazole is 62% and 82%, respectively, and lasts up to 48 hours. This duration of pharmacokinetic action is much longer than that predicted by the half-life (T1/2), which is approximately 1 hour. This effect can be explained by the binding of the drug to the H+/K+ATPase of gastric parietal cells. The magnitude of the inhibitory effect of rabeprazole on acid secretion reaches a plateau after three days of taking rabeprazole. When you stop taking it, secretory activity is restored within 1-2 days.

Effect on serum gastrin concentration

At the beginning of rabeprazole therapy, the concentration of gastrin in the blood serum increases, which is a reflection of the inhibitory effect on the secretion of hydrochloric acid. Gastrin concentrations return to baseline levels usually within 1-2 weeks after cessation of treatment.

Effect on enterochromaffin-like cells

A study of biopsies of the fundus and antrum of more than 500 patients treated with rabeprazole or a comparator for up to 8 weeks found no changes in the morphological structure of enterochromaffin-like (ECL) cells, the severity of gastritis, the incidence of atrophic gastritis, intestinal metaplasia, or the prevalence of Helicobacter pylori infection.

In a study of more than 400 patients receiving rabeprazole 10 mg/day or 20 mg/day for up to 1 year, the incidence of hyperplasia was low and comparable to that of patients receiving omeprazole 20 mg/day. There have been no cases of adenomatous changes or carcinoid tumors observed
in rats.

Other effects

There is currently no evidence that rabeprazole causes systemic effects on the central nervous system (CNS), cardiovascular or respiratory systems. When taken orally at a dose of 20 mg for 2 weeks, rabeprazole has no effect on thyroid function, carbohydrate metabolism, as well as on blood concentrations of parathyroid hormone, cortisol, estrogens, testosterone, prolactin, secretin, glucagon, follicle-stimulating hormone, luteinizing hormone, renin, aldosterone and somatotropin.

Pharmacokinetics

Absorption

Rabeprazole is rapidly absorbed from the intestine and its maximum plasma concentration (Cmax) is reached approximately 3.5 hours after administration of a 20 mg dose. The change in Cmax and area under the pharmacokinetic 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. Neither the time of taking the drug during the day nor antacids affect the absorption of rabeprazole. Taking rabeprazole with fatty foods slows down the absorption of rabeprazole by 4 hours or more, but neither Cmax nor the extent of absorption changes.

Distribution

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

Metabolism

Rabeprazole is metabolized in the body in two ways. A significant part of it is metabolized systemically by a non-enzymatic route with the formation of thioester derivatives. Rabeprazole is also metabolized in the liver via cytochrome P450 to form sulfonic and desmethyl derivatives.

In healthy volunteers, the plasma half-life is approximately 1 hour (varies from 0.7 to 1.5 hours), and the total clearance is 3.8 ml/min/kg.

Removal

After a single oral dose of 20 mg of 14C-labeled rabeprazole, about 90% of rabeprazole is excreted by the kidneys, mainly in the form of carboxylic acid thioester, its glucuronide and in the form of mercapturic acid derivatives. Unchanged rabeprazole is not detected in urine. The remainder of the rabeprazole taken is excreted through the intestines. The total elimination is 99.8%.

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. On average, T1/2 of rabeprazole was 0.82 hours in healthy volunteers, 0.95 hours in patients during hemodialysis and 3.6 hours after hemodialysis. The clearance of rabeprazole 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 healthy volunteers.

Elderly patients

In elderly patients, the elimination of rabeprazole is somewhat slower. After 7 days of rabeprazole 20 mg once daily in elderly subjects, AUC was approximately twice as high and Cmax was increased by 60% compared with young healthy volunteers; There were no signs of rabeprazole accumulation.

CYP2C19 polymorphism

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

Special instructions

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

Razo® 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 using rabeprazole in patients with severe hepatic impairment. The AUC of rabeprazole in patients with severe hepatic impairment is approximately two times higher than in healthy patients.

No dosage adjustment of rabeprazole is required in patients with impaired renal or hepatic function.

Hypomagnesemia

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

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

Bone fractures

Observational studies suggest that proton pump inhibitor 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.

Patients taking rabeprazole for short-term symptomatic treatment of symptoms of GERD and NERD (eg, heartburn) without a prescription should contact their doctor if:

– use of 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 and so on (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 the age of 55 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 blockers or proton pump inhibitors, at the same time as rabeprazole.

If using other medications, patients should consult their pharmacist or physician before starting therapy with over-the-counter rabeprazole.

If the patient is already scheduled for an endoscopic examination, the patient should consult with a physician before using rabeprazole without a prescription.

Rabeprazole should be avoided before a urease breath test.

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

Impact on the ability to drive vehicles and 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 perform other activities that require concentration and speed of psychomotor reactions. However, if drowsiness or dizziness occurs, these activities should be avoided.

Active ingredient

Rabeprazole

Composition

Each 10 mg enteric-coated tablet contains:

active ingredient: rabeprazole sodium 10 mg;

excipients: mannitol, low-substituted hyprolose, heavy magnesium oxide, hypromellose (5cps), sodium lauryl sulfate, talc, magnesium stearate. Shell: zein, triethyl citrate. Enteric coating: methacrylic acid and ethyl acrylate copolymer [1:1] (methacrylic acid copolymer (type C)), triethyl citrate, talc. Shell: Opadry pink 03B54475 (hypromellose 6 cP, titanium dioxide (E171), macrogol-400, red iron oxide dye (E172)). Composition of black ink for writing on a 10 mg tablet: shellac glaze 45%, black iron oxide dye (E172), isopropyl alcohol, n-butanol, propylene glycol, concentrated ammonia solution 28%.

Pregnancy

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. Razo® should not be used during pregnancy unless the expected beneficial effect for the mother outweighs the possible harm to the fetus.
It is not known whether rabeprazole passes into breast milk. Appropriate studies have not been conducted in lactating women. However, rabeprazole was found in the milk of lactating rats, so the drug should not be used by nursing women.

Contraindications

– hypersensitivity to rabeprazole, substituted benzimidazoles or to the auxiliary components of the drug;
– pregnancy;
– breastfeeding period;
– children under 18 years of age.
With caution
Severe renal failure.

Side Effects

Rabeprazole is usually well tolerated by patients. Side effects are generally mild or moderate and are transient.

When taking rabeprazole in clinical studies, the following side effects were observed: headache, abdominal pain, diarrhea, flatulence, constipation, dry mouth, dizziness, rash, peripheral edema.

The frequency of side effects is presented in accordance with the following gradation: very often (>1/10); often (1/10 – 1/100); uncommon (1/100 – 1/1000); rarely (1/1000 – 1/10000); very rare (<1/10000).

Immune system disorders

Rarely – acute systemic allergic reactions.

Blood and lymphatic system disorders

Rarely – thrombocytopenia, neutropenia, leukopenia.

Metabolic and nutritional disorders

Rarely – hypomagnesemia.

Hepatobiliary system disorders

Rarely – increased activity of liver enzymes, hepatitis, jaundice, hepatic encephalopathy.

Renal and urinary tract disorders

Very rarely – interstitial nephritis.

Skin and subcutaneous tissue disorders

Rarely – bullous rashes, urticaria; very rarely – erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders

Rarely – myalgia, arthralgia.

Reproductive system disorders

Very rarely – gynecomastia.

No changes in laboratory parameters were observed while taking rabeprazole.

When taking proton pump inhibitors, the risk of bone fractures may increase (see section “Special Instructions”).

Interaction

Cytochrome 450 system

Rabeprazole, like other proton pump inhibitors (PPIs), is metabolized by the cytochrome P450 (CYP450) system in the liver. In vitro studies with human liver microsomes have shown that rabeprazole is metabolized by the isoenzymes CYP2C19 and CYP3A4.

Studies in healthy volunteers have shown that rabeprazole 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. The AUC and Cmax for rabeprazole increased by 11% and 34%, respectively, and for 14-hydroxy-clarithromycin (the active metabolite of clarithromycin), the 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 provides a stable and long-lasting suppression of gastric juice secretion. Thus, interactions may occur with substances for which absorption is pH dependent. When taken simultaneously with rabeprazole, 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 rabeprazole is coadministered 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, antacids were used in conjunction with rabeprazole. No clinically significant interactions of rabeprazole with aluminum hydroxide gel or magnesium hydroxide were observed.

Eating

In a clinical study, no clinically significant interactions were observed when rabeprazole was administered with a low-fat meal. Taking rabeprazole concomitantly with a fat-rich meal may slow down the absorption of rabeprazole by up to 4 hours or more, but 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 μmol, i.e., at a concentration 50 times the Cmax for healthy volunteers after 20 days of dosing with 20 mg rabeprazole. The degree of inhibition is similar to that of omeprazole for equivalent concentrations.

Methotrexate

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

Overdose

Symptoms. Data on intentional or accidental overdose are minimal. It was reported that taking the drug at a dose of 60 mg 2 times a day or 160 mg once, the side effects were minimal and reversible and did not require medical intervention.
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.

Storage conditions

At a temperature not exceeding 25 °C.
Keep out of the reach of children!

Shelf life

2 years.
Do not use after the expiration date indicated on the package.

Manufacturer

Dr. Reddy’s Laboratories Ltd, India